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Molecular model building studies were conducted to simulate phleomycin-bleomycin (PB) antibiotics and thus assess a hypothetical polyphleomycin-DNA complex proposed earlier. While the latter model was not conclusively proved it was found to be quite consistent with the structure of PB compounds.
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Methods are presented for practicing the viewing of stereoscopic pictures of crystal structures and molecular models without optical aids.
The structure of ribosomal 5 S RNA has been examined using several physical biochemical techniques. Hydrodynamic measurements yield a s020,omega and [eta] of 5.5 x 10(-13) x and 6.9 ml/g, respectively. Other parameters calculated from these values indicate the shape of 5 S RNA is consistent with that of a prolate ellipsoid 160 A in length and 32 A wide. Sedimentation equilibrium results show that 5 S RNA exists as a monomer in the reconstitution buffer with an apparent molecular weight of 44,000. Ultraviolet absorption difference spectra show that approximately 75% of the bases in 5 S RNA are involved in base pairing, and of these base pairs 70% are G-C and 30% are A-U. These results on the overall shape and secondary structure of 5 S RNA have been incorporated with the results of other investigators as to the possible location of single-stranded and double-stranded helical regions, and a molecular model for 5 S RNA is proposed. The molecular model consists of three double helices in the shape of a prolate ellipsoid, with two of the double helical regions at one end of the molecule. The structure is consistent with the available data on the structure and function of 5 S RNA and bears similarity to the molecular model proposed by Osterberg et al. ((1976) Eur. J. Biochem. 68, 481-487) based on small angle x-ray scattering results and the secondary structure proposed by Madison ((1968) Annu. Rev. Biochem. 37, 131-148).
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The crystal structure of pig heart citrate synthase was analyzed at 0.35-nm resolution. Chain tracing was possible and an initial molecular model constructed. The dimensions of the dimer molecule (located on a crystallographic diad) are 7.5 x 6.0 x 9.0 nm. The chain folding is characterized by the predominance of helices and the absence of sheet structure. The electron density accounts for 355 residues per monomer, so that about 80 residues must be disordered in the crystal. The disordered segment in probably N-terminal. The ordered part consists of two closely associated domains, a large domain with 300 residues and a C-terminal domain of 55 residues consisting of 3(anti)parallel helices. The large domain is built from 12 helical segments, some of which are buried in the interior of the molecule. Inhibitor binding studies with citrate and CoA revealed citrate binding sites but showed no electron density for CoA. It is suggested that CoA binds to the disordered, flexible N-terminal domain. Experiments of limited proteolysis with trypsin showed that under conditions a segment of Mr 9000 is cleaved off selectively. The remaining 35 000-Mr part is dimeric.
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A molecular and biochemically plausible model for the excitation process of the sodium pore is suggested. From basic arguments it is concluded that the sodium pore exists in at least three states: the resting state, the sodium conducting state, and the refractory state. They are connected to form a cyclic process. A specification of the different states is given. It is suggested that inactivation of the sodium pore results from a conformational change, which is caused by the transport of a calcium ion through the membrane. The transport carrier is the sodium pore. This assumption can explain the observed calcium influx during stimulation, and the effect of Ca on the rate of inactivation and on the rate, at which sodium conductance shuts off upon repolarization. It cannot give a quantitative explanation for the effect of Ca on the rate of rise, peak sodium conductance, and steady state inactivation. These asects are successfully described by the surface potential hypothesis, which has been published recently. It is concluded, that a combination of both theories gives a rather complete description of the sodium pore. The Ca transport model is discussed quantitatively and in great detail.
A series of molecular events will explain how genetic elements can transpose from one DNA site to another, generate a short oligonucleotide duplication at both ends of the new insertion site, and replicate in the transposition process. These events include the formation of recombinant molecules which have been postulated to be intermediates in the transposition process. The model explains how the replication of bacteriophage Mu is obligatorily associated with movement to new genetic sites. It postulates that all transposable elements replicate in the transposition process so that they remain at their original site while moving to new sites. According to this model, the mechanism of transposition is very different from the insertion and excision of bacteriophage lambda.
BACKGROUND: Papillary thyroid carcinoma (PTC) usually has a favorable prognosis, yet a subset of patients develops persistent, recurrent, or biologically aggressive disease. The clinical relevance of lysine β-hydroxybutyrylation (Kbhb)-related transcriptional programs in PTC remains unclear. Accordingly, this study aimed to characterize Kbhb-related molecular heterogeneity in PTC, construct a prognostic signature, and explore its association with the tumor microenvironment (TME). METHODS: Transcriptomic and clinical data from PTC samples within The Cancer Genome Atlas Thyroid Carcinoma (TCGA-THCA) cohort were analyzed to identify Kbhb-related differentially expressed genes (DEGs), define molecular subtypes, construct a prognostic signature, and characterize tumor microenvironmental features. Single-cell RNA-sequencing data from PTC were further used to explore the cellular distribution of representative genes. RESULTS: We identified 51 Kbhb-related DEGs in PTC and defined two Kbhb molecular subtypes. The Kbhb_C2 subtype showed shorter progression-free interval (PFI) and a more immune- and stroma-enriched microenvironment. A six-gene prognostic signature comprising TARID, CDSN, PIMREG, KLRC1, SYT13, and NPR3 was then established. High-risk patients had significantly worse PFI in the full, training, and testing cohorts, with 1-, 3-, and 5-year areas under the curve (AUCs) of 0.715, 0.793, and 0.771, respectively, in the full cohort. High-risk tumors also exhibited higher stromal, immune, and ESTIMATE scores, altered immune infiltration, and increased expression of multiple immune checkpoint molecules. Single-cell analysis confirmed distinct cell-type-specific expression patterns of representative genes. CONCLUSIONS: Kbhb-related transcriptional programs define clinically relevant molecular heterogeneity in PTC and are closely associated with prognosis and TME remodeling. The identified six-gene signature provides a biologically interpretable framework for risk stratification in PTC.
A mixture of fragments D, derived from fibrinogen by plasmic degradation, was S-reduced and carboxymethylated. Individual chains were separated by gel filtration on Sephadex G-100 and characterized by peptide mapping, N-terminal amino acid analysis, polyacrylamide electrophoresis in sodium dodecyl sulfate, and amino acid composition. It was demonstrated that all D species contain the same alpha- and beta-chain remnants, having mol. wts of 10 000 and 45 000, respectively. Their heterogeneity was shown to be caused by the gradual degradation of the gamma-chain at its C-terminal end. Denatured fragment D was further degraded with plasmin in the presence of 2 M urea. One beta- (mol. wt 17 000) and two gamma-fragments (mol. wts 5000 and 6000) were split from fragment D, in addition to non-characterized small peptides, leaving behind a plasmin-resistant core, designated as fragment d. Fragment d was in turn reduced and carboxymethylated, and the resulting constituent chains were isolated by chromatography on carboxymethyl-cellulose and Sephadex G-100. The reduced alpha-, beta- and gamma-chain remnants of fragment d were found to have been derived from the N-terminal portion of fragment D and have estimated mol. wts of 9000, 24 000 and 13 000, respectively. A tentative scheme for the conversion of an early fragment D into the core fragment d is proposed. Our results conclusively support the model of asymmetric degradation of fibrinogen, according to which 2 mol of monomeric fragment D are produced from 1 mol of fibrinogen.
Using information from conformation-predicting algorithms and X-ray data, a possible mode of structural evolution from an ancestral molecule of about 28 residues to bacterial ferredoxins and rubredoxins is suggested. The possibility of a further evolutionary pathway leading to flavodoxin-like proteins is also indicated.
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Codon recognition occurs during protein synthesis with the aminoacyl-tRNA bound in the recognition (or R) tRNA-binding site. The recognition site is thought to be located on the external surface of the smaller ribosomal subunit distal from the interface between subunits, where the aminoacyl (A) and peptidyl (P) tRNA-binding sites are located. A molecular model describing the switching of the aminoacyl-tRNA from the R site to the A site is proposed. Details of the model include codon recognition at the R site by an aminoacyl-tRNA with its anticodon loop in the 5' stacked conformation; movement of the aminoacyl-tRNA from the R site to the A site by a switching in the anticodon loop from the 5' stacked conformation to the 3' stacked conformation; and recognition of the correct reading frame by a base-pairing interaction between the A and P site tRNAs that involves trans pairing of the invariant bases U-33 of both molecules.
Space-filling molecular models of selected phytohormones and DNA, employed as described herein, illustrate possible in vivo stereochemical recognition between nucleic acids and intercalated phytohormones. In this regard, the absolute chirality of certain phytohormones, and that of DNA may be essential for the recognition process. It is speculated further that the specific interactions shown by molecular models have significance in the evolution of plant regulatory mechanisms.
It is contended that redundant repressed tRed) with carcinogens in adult cells. Supportive evidence, especially from molecular model building, is presented for a mechanism of tRNA methylation. In this mechanism the adenine moiety of S-adenosyl-L-methionine base-pairs with uracil for all tRNA methylations. Furthermore it is proposed that such methylations are required during the transcription of a tRNA molecule in order to limit the number of possible conformers that can occur before further development of the molecule takes place. This theory of the function for methyl groups is discussed in the light of the properties found for hypomethylated tRNAs.