SEARCH · PubMed Health

Results for “Solvent accessibility”

Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 667 records · Page 37Linked to original sources

PubMed2000

Comparative X-ray analysis of the un-liganded fosfomycin-target murA.

MurA, an essential enzyme for the synthesis of the bacterial cell wall, follows an induced-fit mechanism. Upon substrate binding, the active site forms in the interdomain cleft, involving movements of the two domains of the protein and a reorientation of the loop Pro112-Pro121. We compare two structures of un-liganded MurA from Enterobacter cloacae: a new orthorhombic form, solved to 1.80 A resolution, and a monoclinic form, redetermined to 1.55 A resolution. In the monoclinic form, the loop Pro112-Pro121 stretches into solvent, while in the new form it adopts a winded conformation, thereby reducing solvent accessibility of the critical residue Cys115. In the interdomain cleft a network of 27 common water molecules has been identified, which partially shields negative charges in the cleft and stabilizes the orientation of catalytically crucial residues. This could support substrate binding and ease domain movements. Near the hinge region an isoaspartyl residue has been recognized, which is the product of post-translational modification of the genetically encoded Asn67-Gly68. The homogeneous population with L-isoaspartate in both structures suggests that the modification in Enterobacter cloacae MurA is not a mere aging defect but rather the result of a specific in vivo process.

Alkyl and Aryl Transferases↗

PubMed1994

A detailed comparison of the refined structures of cytochrome c3 molecules from two strains in Desulfovibrio vulgaris: the relationship between the heme structures and their redox properties.

The refined structures of the cytochrome c3 molecules from Desulfovibrio vulgaris Miyazaki and Hildenborough have been compared in detail. Though there are no significant differences of the overall structure and spatial arrangement of four heme groups between two molecules, there are some unique features with regard to the local structures near the heme pockets. Two of the heme groups show significant differences including a hydrogen bonding scheme between the imidazole rings and water molecules in heme pocket. The water molecule near the heme 1 pocket in Miyazaki cytochrome c3 is replaced by the C delta 1 atom of Leu9 in the Hildenborough structure. The rotation around the C alpha-C beta bond of Leu9 results in the increase of the solvent accessibility of the portion of the heme 1 edge. On the other hand, in heme3 one water molecule is additionally included in the hydrogen bonding network with a N delta 1 atom of the imidazole ring and carbonyl oxygen atom of the main chain in Hildenborough cytochrome c3. This additional hydrogen bonding network will contribute to the possible passage between the imidazole ring and the molecular surface. These features have been related to the upfield shift of the C2 proton signals of NMR spectra and the low redox potentials of the cytochrome c3 molecules of Desulfovibrio vulgaris Hildenborough in comparison with those from Miyazaki.

Amino Acid Sequence↗

PubMed2001

Interaction of chicken liver basic fatty acid-binding protein with fatty acids: a 13C NMR and fluorescence study.

Two different groups of liver fatty acid-binding proteins (L-FABPs) are known: the mammalian type and the basic type. Very few members of this second group of L-FABPs have been characterized and studied, whereas most of the past studies were concerned with the mammalian type. The interactions of chicken liver basic fatty acid-binding protein (Lb-FABP) with 1-(13)C-enriched palmitic acid (PA) and oleic acid (OA) were investigated by (13)C NMR spectroscopy. Samples containing fatty acids (FA) and Lb-FABP at different molar ratios exhibited only a single carboxylate resonance corresponding to bound FA, and showed a binding stoichiometry of 1:1 both for PA and for OA. Fluorescence spectroscopy measurements yielded the same binding stoichiometry for the interaction with cis-parinaric acid [K(d) = 0.38(4) microM]. Competition studies between cis-parinaric acid and the natural ligands indicated a decreasing affinity of chicken Lb-FABP for PA, OA, and retinoic acid (RA). (13)C NMR proved that pH and ionic strength affect complex stability. The carboxyl signal intensity reversibly decreased upon lowering the pH up to 5. The pH dependence of the bound carboxyl chemical shift yielded an apparent pK(a) of 4.8. A decrease of the integrated intensity of the bound carboxylic signal in the NMR spectra was observed while increasing the chloride ion concentration up to 200 mM. This body of evidence indicates that the bound FA is completely ionized at pH 7.4, that its polar head is positioned in a solvent-accessible region, that a FA-protein strong ionic bond is not present, and that high ionic strength causes the release of the bound FA. The reported results show that, insofar as the number of bound ligands and its relative affinity for different FAs are concerned, chicken Lb-FABP is remarkably different from the mammalian liver FABPs, and, within its subfamily, that it is more similar to catfish Lb-FABP while it behaves quite differently from shark or axolotl Lb-FABPs.

Animals↗

PubMed2000

The structural basis for molecular recognition by the vitamin B 12 RNA aptamer.

Previous solution structures of ligand-binding RNA aptamers have shown that molecular recognition is achieved by the folding of an initially unstructured RNA around its cognate ligand, coupling the processes of RNA folding and binding. The 3 A crystal structure of the cyanocobalamin (vitamin B12) aptamer reported here suggests a different approach to molecular recognition in which elements of RNA secondary structure combine to create a solvent-accessible docking surface for a large, complex ligand. Central to this structure is a locally folding RNA triplex, stabilized by a novel three-stranded zipper. Perpendicular stacking of a duplex on this triplex creates a cleft that functions as the vitamin B12 binding site. Complementary packing of hydrophobic surfaces, direct hydrogen bonding and dipolar interactions between the ligand and the RNA appear to contribute to binding. The nature of the interactions that stabilize complex formation and the possible uncoupling of folding and binding for this RNA suggest a strong mechanistic similarity to typical protein-ligand complexes.

Base Pairing↗

PubMed1999

Structural analysis of a non-contiguous second-site revertant in T4 lysozyme shows that increasing the rigidity of a protein can enhance its stability.

The mutation Glu108-->Val (E108V) in T4 lysozyme was previously isolated as a second-site revertant that specifically compensated for the loss of function associated with the destabilizing substitution Leu99-->Gly (L99G). Surprisingly, the two sites are 11 A apart, with Leu99 in the core and Glu108 on the surface of the protein. In order to better understand this result we have carried out a detailed thermodynamic, enzymatic and structural analysis of these mutant lysozymes as well as a related variant with the substitution Leu99-->Ala. It was found that E108V does increase the stability of L99G, but it also increases the stability of both the wild-type protein and L99A by essentially equal amounts. The effects of E108V on enzymatic activity are more complicated. The mutation slightly reduces the maximal rate of cell wall hydrolysis of wild-type, L99G and L99A. At the same time, L99G is an unstable protein and rapidly loses activity during the course of the assay, especially at temperatures above 20 degrees C. Thus, even though the double mutant L99G/E108V has a slightly lower maximal rate than L99G, over a period of 20-30 minutes it hydrolyzes more substrate. This decrease in the rate of thermal inactivation appears to be the basis of the action of E108V as a second-site revertant of L99G. Mutant L99A creates a cavity of volume 149 A(3). Instead of enlarging this cavity, mutant L99G results in a 4-5 A displacement of part of helix F (residues 108-113), creating a solvent-accessible declivity. In the double mutant, L99G/E108V, this helix returns to a position akin to wild-type, resulting in a cavity of volume 203 A(3). Whether the mutation Glu108-->Val is incorporated into either wild-type lysozyme, or L99A or L99G, it results in a decrease in crystallographic thermal factors, especially in the helices that include residues 99 and 108. This increase in rigidity, which appears to be due to a combination of increased hydrophobic stabilization plus a restriction of conformational fluctuation, provides a structural basis for the increase in thermostability.

Amino Acid Substitution↗

PubMed1999

The molten globule state of a chimera of human alpha-lactalbumin and equine lysozyme.

The molten globule state of equine lysozyme is more stable than that of alpha-lactalbumin and is stabilized by non-specific hydrophobic interactions and native-like hydrophobic interactions. We constructed a chimeric protein which is produced by replacing the flexible loop (residues 105-110) in human alpha-lactalbumin with the helix D (residues 109-114) in equine lysozyme to investigate the possible role of the helix D for the high stability and native-like packing interaction in the molten globule state of equine lysozyme. The stability of the molten globule state formed by the chimeric protein to guanidine hydrochloride-induced unfolding is the same as that of equine lysozyme and is substantially greater than that of human alpha-lactalbumin, although only six residues come from equine lysozyme. Our results also suggest that the non-native interaction in the molten globule state of alpha-lactalbumin changes to the native-like packing interaction due to helix substitution. The solvent-accessibility of the Trp residues in the molten globule state of the chimeric protein is similar to that in the molten globule state of equine lysozyme in which packing interaction around the Trp residues in the native state is partially preserved. Therefore, the helix D in equine lysozyme is one of the contributing factors to the high stability and native-like packing interaction in the molten globule state of equine lysozyme. Our results indicate that the native-like packing interaction can stabilize the rudimentary intermediate which is stabilized by the non-specific hydrophobic interactions.

Acrylamide↗

PubMed1991

Percutaneous penetration of drugs: a quantitative structure-permeability relationship study.

Human skin permeation data taken from the literature were analyzed for quantitative relationships with physicochemical properties and structural descriptors. No correlations exist with molecular weights and solvent-accessible surface areas. In most cases, skin permeation was inversely correlated with the parameter delta log Poct-hep (i.e., log Poctanol minus log Pheptane), which is mainly a measure of the H-bond donor acidity of the solutes. Lipophilicity itself, as expressed by log Poctanol, also contributes positively to skin permeation in some cases. The results of this quantitative structure-permeability relationship study are interpreted in terms of a unified mechanistic model whereby drugs can permeate via an intercellular route (correlation with both delta log Poct-hep and log Poct) and/or a transcellular route (correlation with log Poct only).

Administration, Topical↗

PubMed2000

The serine protease inhibitor canonical loop conformation: examples found in extracellular hydrolases, toxins, cytokines and viral proteins.

Methods for the prediction of protein function from structure are of growing importance in the age of structural genomics. Here, we focus on the problem of identifying sites of potential serine protease inhibitor interactions on the surface of proteins of known structure. Given that there is no sequence conservation within canonical loops from different inhibitor families, we first compare representative loops to all fragments of equal length among proteins of known structure by calculating main-chain RMS deviation. Fragments with RMS deviation below a certain threshold (hits) are removed if residues have solvent accessibilities appreciably lower than those observed in the search structure. These remaining hits are further filtered to remove those occurring largely within secondary structure elements. Likely functional significance is restricted further by considering only extracellular protein domains. By comparing different canonical loop structures to the protein structure database, we show that the method is able to detect previously known inhibitors. In addition, we discuss potentially new canonical loop structures found in secreted hydrolases, toxins, viral proteins, cytokines and other proteins. We discuss the possible functional significance of several of the examples found, and comment on implications for the prediction of function from protein 3D structure.

Amino Acid Sequence↗

PubMed1997

The P4-P6 domain directs higher order folding of the Tetrahymena ribozyme core.

The active site of group I self-splicing introns occurs at the interface of two proposed structural domains. In the Tetrahymena intron, half of the catalytic core resides within the independently-folding P4-P6 domain while the other half belongs to a putative domain that includes helices P3, P7, P8, and P9 (P3-P9). To determine whether the P3-P9 region of the intron can also fold independently, we used Fe(II)-EDTA and dimethyl sulfate to probe the solvent accessibility of separate fragments of the Tetrahymena intron. These RNAs self-assemble into an active complex in trans, enabling analysis of their structural features both alone and within the complex. Our results show that while the P3-P9 region of the intron retains its secondary structure, most of the tertiary interactions within this region do not form stably in the absence of the P4-P6 domain. This indicates that the P4-P6 domain induces folding in the P3-P9 region, organizing the catalytic cleft between them. Thus the P4-P6 domain provides a scaffold for the folding of the Tetrahymena intron core.

Animals↗

PubMed1997

Alloreactive T cell recognition of MHC class I molecules: the T cell receptor interacts with limited regions of the MHC class I long alpha helices.

T cells recognize MHC-bound peptide, suggesting that the TCR contacts surface MHC residues adjacent to bound peptide, but the extent of MHC contact is not known. T cells also may recognize peptide-induced conformational changes, and alloreactive T cells may recognize surface MHC structures in addition to or independent of bound peptide. Alloreactive T cells are not intentionally biased to recognize particular MHC-bound peptides and should reveal general constraints for TCR binding. To map TCR binding sites, we tested 60 HLA-B7 site-specific mutations with 12 alloreactive CTL clones that express different TCRs. The alloreactive CTL clones recognize solvent-accessible residues that cluster between positions 62 to 80 and 150 to 170. Thus, TCRs contact largely overlapping MHC structures in the alpha1 and alpha2 domain long alpha helices. The dimensions and location of this site are consistent with recently reported crystallographic studies of two TCR/peptide-MHC class I complexes. In contrast to TCR, Abs recognize multiple discrete epitopes that encircle the peptide binding groove and potentially encompass the entire surface of the MHC molecule. Our data suggest that TCRs dock with a common discrete MHC site and that recent crystallographic models are likely to be generally applicable to T cell recognition of peptide-MHC class I complexes.

Amino Acid Sequence↗

PubMed1991

Three-dimensional structure of murine anti-p-azophenylarsonate Fab 36-71. 2. Structural basis of hapten binding and idiotypy.

Comparison between the structures and solvent-accessible surfaces of the antigen-binding fragments of two murine anti-p-azophenylarsonate monoclonal antibodies, one bearing a major cross-reactive idiotype of A/J strain mice (36-71) and one lacking the idiotype (R19.9; Lascombe et al., 1989), highlight the structural basis for the determination of hapten affinity and idiotypy. Since the sequence of R 19.9 is identical with the germline-encoded sequence at 16 positions in both heavy-chain and light-chain variable regions where somatic mutations and junctional differences have occurred to produce the 36-71 sequence, the structure of R 19.9 can be used to model the structure of the germline-encoded antibody (36-65) in the regions around these sites. These 16 sequence differences exclude the third heavy-chain complementarity-determining region because R 19.9 utilizes a D gene segment not associated with the predominant idiotype, which is 4 residues longer than the canonical D gene segment utilized in the sequences of 36-71 and 36-65. This difference between the structures of R 19.9 and 36-71 does not affect the validity of using the structure of R 19.9 to model the structure of 36-65 since the third heavy-chain complementarity-determining region is highly solvent-exposed in both 36-71 and R 19.9, and does not interact with any of these 16 sites. Comparing the structures of 36-71 and R 19.9 suggests that only three of the differences in the heavy-chain sequences, and three of the differences in the light-chain sequences of 36-71 and 36-65, increase the affinity for hapten.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗

PubMed1994

Epitopes on proteinase-3 recognized by antibodies from patients with Wegener's granulomatosis.

The 228 amino acid primary sequence of proteinase-3 (PR3) was studied for antigenic epitopes, which react with IgG Ab in sera of patients with Wegener's granulomatosis, by synthesizing overlapping 7 mers of PR3 linear sequence on pins. Main regions of linear sequence reactivity included GHEAQPH (at residues 4-10), QPHSRPY (8-14), TQEPTQQ (65-71), ATVQLPQ (108-114), QLPQQDQ (111-117), PVPHGTQ (118-124), RVGAHDP (132-138), FCRPHNI (154-160), PRRKAGI (165-171), FGDSGGP (173-179), and IDSFVIW (189-195). All of these regions were surface accessible and seemed to be on the outside of the molecule. By substituting a glycine or an alanine for each residue within each reactive epitope, we identified the arginine at 12, valine at 119, proline at 120, histidine at 121, arginine at 132, alanine at 135, histidine at 136, and glycine at 178 as major immunodominant single residues that contribute to antigenic determinants. Visualization of these reactive regions on a three-dimensional computer-generated carbon PR3 trace diagram showed that one aspect of the molecule on the inferolateral surface comprised most of the antigenic regions. Two peptides, ATVQLPQ and RVGAHDP, when preincubated with Wegener's granulomatosis sera, produced almost complete inhibition of Wegener's granulomatosis IgG Abs either binding to PR3 on the ELISA plate or by reacting with polymorphonuclear leukocyte azurophilic granules in immunofluorescence assays for cANCA. FGDSGGP (at residues 173-179), one epitope that was recognized by Wegener's patient sera Abs, included part of the active catalytic triad for PR3. Rabbit Abs against the PR3 peptides ATVQLPQ or RVGAHDP showed a cANCA cytoplasmic granular pattern of immunofluorescence staining when they were incubated with polymorphonuclear leukocytes. These findings indicate that it is possible to identify various antigenic sites on PR3 by using overlapping 7 mers of portions of the solvent, accessible linear sequence.

Amino Acid Sequence↗

PubMed2001

Prediction of a 12-residue loop in bovine pancreatic trypsin inhibitor: effects of buried water.

The x-ray conformations of 5-, 7-, 9-, and 12-residue loops in bovine pancreatic trypsin inhibitor (BPTI) were predicted by the use of multiple independent Monte Carlo simulating annealing (MCSA) runs starting from random conformations. Four buried water molecules interacted with a 12-residue loop that started at residue 8 and ended at residue 19, and that included the binding region. The final conformation at the end of an MCSA run was characterized. Solvation free energy based on the solvent accessible surface area was included in the energy function at low simulated annealing temperatures. Conformational states were interactively separated by a recently developed algorithm. Computed loops were characterized in terms of total energy, and backbone and side chain root mean square deviations (RMSDs) between computed native loop conformations and the x-ray conformation. The 12-residue loop was computed with and without buried water [called WL12(8-19) and L12(8-19), respectively]. The backbone was reliably and reproducibly computed to within 1.1 A in L12(8-19) and 0.9 A in WL12(8-19). L12(8-19) required significantly more MCSA runs to achieve the same level of reproducibility as WL12(8-19). Based on the size of the cluster of low energy native loop conformations, and the computational effort, WL12(8-19) had greater entropy. In calculations of 7-, 9-, and 12-residue loops without buried water, the effects of buried water became obvious in the 12-residue loop calculation, which interacted with all four buried water molecules. Nearly all conformations of the native loop conformer had a hydrogen bond between the Lys 15 side chain and the backbone of Gly 12, Pro 13, and Cys 14, which may have implications in the rate of exchange of buried water with bulk solvent and in protein folding. The present version of MCSA program was more efficient than earlier versions.

Animals↗

PubMed2003

Solvent protection of the hammerhead ribozyme in the ground state: evidence for a cation-assisted conformational change leading to catalysis.

Tertiary folding of the hammerhead ribozyme has been analyzed by hydroxyl radical footprinting. Three hammerhead constructs with distinct noncore sequences, connectivities, and catalytic properties show identical protection patterns, in which conserved core residues (G5, A6, U7, G8, and A9) and the cleavage site (C17, G1.1, and U1.2) become reproducibly protected from nucleolytic attack by radicals. Metal ion titrations show that all protections appear together, suggesting a single folding event to a common tertiary structure, rather than an ensemble of different folds. The apparent binding constants for folding and catalysis by Mg(2+) are lower than those for Li(+) by 3 orders of magnitude, but in each case the protected sites are identical. For both Mg(2+) and Li(+), the ribozyme folds into the protected tertiary structure at significantly lower cation concentrations than those required for cleavage. The sites of protection include all of the sites of reduced solvent accessibility calculated from two different crystal structures, including both core and noncore nucleotides. In addition, experimentally observed protected sites include additional sequences adjacent to those predicted by the crystal structures, suggesting that the solution structure may be folded into a more compact shape. A 2'-deoxy substitution at G5 abolishes all protection, indicating that the 2'-OH is essential for folding. Together, these results support a model in which low concentrations of metal ions fold the ribozyme into a stable ground state tertiary structure that is similar to the crystallographic structures, and higher concentrations of metal ions support a transient conformational change into the transition state for catalysis. These data do not themselves address the issue as to whether a large- or small-scale conformational change is required for catalysis.

Magnesium↗

PubMed2004

Experimental indication for the existence of multiple Trp rotamers in von Willebrand Factor A3 domain.

The first step in both normal haemostasis and arterial thrombosis is the interaction between collagen, von Willebrand factor (vWF), and glycoprotein Ib. The A3 domain of vWF forms the principal binding site for collagen type I and type III. Inhibition of the vWF-collagen interaction by an anti-human vWF monoclonal antibody (MoAb) 82D6A3 can be a potential way to prevent arterial thrombosis. Identification of the epitope of MoAb 82D6A3 showed recently that the consensus sequence SPWR obtained by phage display could adopt the conformation of the discontinuous epitope. Modelling showed that Trp982 in the vWF had to obtain a more solvent accessible conformation. We performed a detailed fluorescence study of Trp982 in the vWF A3. Using the method described by Hellings et al. (Biophys J 2003;85:1894-1902), we were able to identify two different low-energy Trp982 rotamers and to link them with their experimentally derived fluorescence lifetimes. Fluorescence anisotropy showed no interconversion in the nanosecond timescale between the two different rotameric states. With these experiments, we gather strong indications for the existence of an exposed rotamer conformation and a rotamer that corresponds to the one observed in the X-ray structure. These results strongly support the modeling work (Vanhoorelbeke et al., J Biol Chem 2003;278:37815-37821).

Binding Sites↗

PubMed1996

New conformational properties induced by the replacement of Tyr-64 in Desulfovibrio vulgaris Hildenborough ferricytochrome c553 using isotopic exchanges monitored by mass spectrometry.

In order to study the conformational stability induced by the replacement of Tyr-64 in Desulfovibrio vulgaris Hildenborough (DvH) cytochrome c553, fast peptic digestion of deuterated protein followed by separation and measurement of related peptides using liquid chromatography coupled to electrospray ionization mass spectrometry was performed. We show that the H-bonding and/or solvent accessibility properties were modified by the single-site mutation. The mutant proteins can be classified into two groups: the Y64F and Y64L mutants with nearly unchanged deuterium incorporation compared to the wild-type protein and the Y64S, Y64V and Y64A mutants with increased deuterium incorporation. The 70-74 peptide was the most affected by mutation of Tyr-64, the phenylalanine mutant inducing slight stabilization whereas the serine mutant was significantly destabilized. In addition, from the analysis of the overlapping 37-57 and 38-57 peptides we can conclude that the amide proton of Tyr-38 has been replaced by deuterium in all proteins.

Cytochrome c Group↗

PubMed1988

Yeast iso-1-cytochrome c. A 2.8 A resolution three-dimensional structure determination.

A molecular replacement approach, augmented with the results of predictive modeling procedures, solvent accessibility studies, packing analyses and translational coefficient searches, has been used to elucidate the 2.8 A (1 A = 0.1 nm) resolution structure of yeast iso-1-cytochrome c. An examination of the polypeptide chain folding of this protein shows it to have unique conformations in three regions, upon comparison with the structures of other eukaryotic cytochromes c. These include: residues -5 to +1 at the N-terminal end of the polypeptide chain, which are in an extended conformation and project in large part off the surface of the protein; residues 19 to 26, which form a surface beta-loop on the His18 ligand side of the central heme group; and, the C-terminal end of the helical segment composed of residues 49 to 56, which serves to form a part of the heme pocket. Structural studies also show that the highly reactive sulfhydryl group of Cys102 is buried within a hydrophobic region in the monomer form of yeast iso-1-cytochrome c. Dimerization of yeast iso-1-cytochrome c through disulfide bond formation between two such residues would require a substantial conformational change in the C-terminal helix of this protein. Another unique structural feature, the trimethylated side-chain of Lys72, is located on the surface of yeast iso-1-cytochrome c near the solvent-exposed edge of the bound heme prosthetic group. On the basis of the results of these and other structural studies, an analysis of the spatial conservation of structural features in the heme pocket of eukaryotic cytochromes c has been conducted. It was found that the residues involved could be divided into three general classes. The current structural analyses and additional modeling studies have also been used to explain the altered functional properties observed for mutant yeast iso-1-cytochrome c proteins.

Amino Acid Sequence↗

PubMed2004

Conservation and covariance in PH domain sequences: physicochemical profile and information theoretical analysis of XLA-causing mutations in the Btk PH domain.

Mutations that cause X-linked agammaglobulinemia (XLA) appear throughout the Bruton tyrosine kinase (Btk) sequence, including the pleckstrin homology (PH) domain. To analyze the basis of this disease with respect to protein structure, we studied the relationships between PH domain sequences and structures by comparing sequence-based profiles of physicochemical properties and solvent accessibility profiles. The diversity of the distribution of amino acids was measured by calculating entropies for sequences containing mutations at different positions in multiple sequence alignments. Mutual information was calculated to quantify positional covariation. Eight conserved extrema were apparent in all profiles. The majority of the XLA disease-causing mutations in the Btk PH domain were found at positions having significant mutual information, indicating that there are covariant constraints for both structure and function. Together with additional structural analyses, all the XLA mutations that were analyzed could be explained at the molecular level. The method developed here is applicable to the design of mutations for protein engineering.

Agammaglobulinemia↗