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L H Pearl

Publications and source records attributed to L H Pearl.

65 records · Page 4Linked to original sources
PubMed1987

Molecular modelling of the interactions of tetra-(4-N-methylpyridyl) porphin with TA and CG sites on DNA.

The molecular structure of the DNA-intercalating ligand tetra-(4-N-methylpyridyl) porphin has been determined by X-ray crystallography. The porphyrin has a precise centre of symmetry; the central core is planar, with the N-methylpyridyl groups inclined to it at angles of 66-72 degrees. Molecular modelling of this structure into TpA and CpG sites of intercalated DNA, has been performed, and approximate energetics calculated. It has been shown that only the CpG site can have full ligand intercalation, since the thymine methyl group sterically hinders such geometry at TpA sites. Modelling indicates the importance of electrostatic effects in the low-energy forms of intercalated and part-intercalated complexes at both sequences.

Base Composition↗
PubMed1987

The crystal structure of the DNA-binding drug berenil: molecular modelling studies of berenil-DNA complexes.

The crystal structure of the DNA minor-groove DNA-binding drug berenil has been determined. Molecular-modelling techniques have been used to establish plausible binding modes of the structure to A-T sequences. These have shown that specific hydrogen bonds are possible between the amidine groups of the drug molecule and 02 atoms of thymine, although global energy minimisations tended to emphasise electrostatic interactions with phosphate groups rather than these hydrogen bonds with bases.

Amidines↗
PubMed1987

The catalytic mechanism of aspartic proteinases.

The highly symmetric active site of an aspartic proteinase, endothiapepsin, binds a water molecule ideally situated for nucleophilic attack on a substrate peptide bond whose distortion from planarity is stabilised by interactions of the substrate with the extended binding cleft. The apparent electrophilicity of the catalysis results from this distortion. The scissile peptide bond is orientated with the carbonyl oxygen hydrogen bonding to the tip of the beta-hairpin 'flap' which lies over the cleft. Nucleophilic attack by the bound water leads to a tetrahedral intermediate similar to observed complexes with hydroxyl inhibitors and stabilised by hydrogen bonds with the flap.

Aspartic Acid Endopeptidases↗
PubMed1987

Crystallographic studies of reduced bond inhibitors complexed with an aspartic proteinase.

To aid in the design of an effective inhibitor to human renin, it is essential to have a detailed knowledge of how this aspartic proteinase interacts with its substrate, angiotensinogen. Human renin shows a stringent specificity toward the Leu-Val bond in its natural substrate. The minimal length for an effective substrate has been characterised as an octapeptide sequence derived from the amino terminal portion of angiotensinogen (residues 6----13): His-Pro-Phe-His-Leu-Val-Ile-His (Leu-Val is the scissile bond). This suggests that renin has a fairly extensive active site cleft, as has been observed in homologous enzymes whose three-dimensional structures have been solved using x-ray diffraction methods. The homologous fungal aspartic proteinase, endothiapepsin, has been cocrystallised with human renin inhibitors of the type His-Pro-Phe-His-Leu-R-Val-Ile-His, where R indicates a reduced carbonyl analogue of the scissile peptide bond. The three-dimensional crystallographic structures of two complexes of endothiapepsin with an inhibitor have been solved. The details of inhibitor binding at the active site cleft of endothiapepsin are described. These data allow a rational approach to the design of novel renin inhibitors, through studies of these inhibitors in a three-dimensional model of human renin constructed in our laboratory.

Amino Acid Sequence↗
PubMed1986

Origins of stereospecificity in DNA damage by anti-benzo[a]pyrene diol-epoxides. A molecular modelling study.

A general computational procedure for the modelling of intercalated DNA-ligand complexes has been developed, and is used here to model intercalated complexes of the (+)-anti and (-)-anti enantiomers of benzo[a]pyrene diol-epoxide (BPDE) with cytosine-3',5'-guanosine double-stranded DNA sequences (dCpG). Results are presented indicating differences between the behaviours of the two enantiomers which have implications for the understanding of the stereospecificity of DNA strand breakage by benzo[a]pyrene diol-epoxides.

7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide↗
PubMedDate not supplied

High resolution X-ray analyses of renin inhibitor-aspartic proteinase complexes.

Inhibitors of the conversion of angiotensinogen to the vasoconstrictor angiotensin II have considerable value as antihypertensive agents. For example, captopril and enalapril are clinically useful as inhibitors of angiotensin-converting enzyme. This has encouraged intense activity in the development of inhibitors of kidney renin, which is a very specific aspartic proteinase catalysing the first and rate limiting step in the conversion of angiotensinogen to angiotensin II. The most effective inhibitors such as H-142 and L-363,564 have used non-hydrolysable analogues of the proposed transition state, and partial sequences of angiotensinogen (Table 1). H-142 is effective in lowering blood pressure in humans but has no significant effect on other aspartic proteinases such as pepsin in the human body (Table 1). At present there are no crystal structures available for human or mouse renins although three-dimensional models demonstrate close structural similarity to other spartic proteinases. We have therefore determined by X-ray analysis the three-dimensional structures of H-142 and L-363,564 complexed with the aspartic proteinase endothiapepsin, which binds these inhibitors with affinities not greatly different from those measured against human renin (Table 1). The structures of these complexes and of that between endothiapepsin and the general aspartic proteinase inhibitor, H-256 (Table 1) define the common hydrogen bonding schemes that allow subtle differences in side-chain orientations and in the positions of the transition state analogues with respect to the active-site aspartates.

Angiotensinogen↗
PubMedDate not supplied

A structural model for the retroviral proteases.

In many retroviruses the 5' end of the pol gene codes for a protease vital for the processing of the gag polyprotein into the separate core proteins. In some viruses this protease is encoded at the 3' end of the gag gene, or between the gag and pol genes in a different reading frame to either. A sequence, Asp-Thr-Gly, which is conserved in retroviral proteases is also conserved in the active sites of aspartic proteases, an observation which has led to the suggestion that the retroviral proteases could belong to this family. We have examined the sequences of the aspartic and retroviral protease families, using pattern-recognition, structure prediction and molecular modelling techniques, and conclude that the viral protease sequences probably correspond to a single domain of an aspartic protease and may function in a dimeric form. We have constructed a model of the pol-protease of human immunodeficiency virus 1 (HIV-1) to test this hypothesis.

Amino Acid Sequence↗
PubMedDate not supplied

The mechanism of DNA repair by uracil-DNA glycosylase: studies using nucleotide analogues.

2',4'-Dideoxy-4'-methyleneuridine incorporated into oligodeoxynucleotides forms regular B-DNA duplexes as shown by Tm and CD measurements. Such oligomers are not cleaved by the DNA repair enzyme, UDG, which cleaves the glycosylic bond in dU but not in dT nor in dC nucleosides in single stranded and double stranded DNA. Differential binding of oligomers containing carbadU, 4'-thiodU, and dU residues to wild type and mutant UDG proteins identify an essential role for the furanose 4'-oxygen in recognition and cleavage of dU residues in DNA.

Base Sequence↗