Survey of the Intermolecular Disulfide Bonds Observed in Protein Crystal Structures Deposited in the Protein Data Bank
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ABSTRACT:
SUBMITTER: Carugo O
PROVIDER: S-EPMC9323673 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Nearly all the macromolecular three-dimensional structures deposited in Protein Data Bank were determined by either crystallographic (X-ray) or Nuclear Magnetic Resonance (NMR) spectroscopic methods. This paper reports a systematic comparison of the crystallographic and NMR results deposited in the files of the Protein Data Bank, in order to find out to which extent these information can be aggregated in bioinformatics. A non-redundant data set containing 109 NMR - X-ray structure pairs of nearly identical proteins was derived from the Protein Data Bank. A series of comparisons were performed by focusing the attention towards both global features and local details. It was observed that: (1) the RMDS values between NMR and crystal structures range from about 1.5 Å to about 2.5 Å; (2) the correlation between conformational deviations and residue type reveals that hydrophobic amino acids are more similar in crystal and NMR structures than hydrophilic amino acids; (3) the correlation between solvent accessibility of the residues and their conformational variability in solid state and in solution is relatively modest (correlation coefficient = 0.462); (4) beta strands on average match better between NMR and crystal structures than helices and loops; (5) conformational differences between loops are independent of crystal packing interactions in the solid state; (6) very seldom, side chains buried in the protein interior are observed to adopt different orientations in the solid state and in solution.
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Project description:The ? Rz and Rz1 proteins are the subunits of the spanin complex, required for the disruption of the outer membrane during host lysis. Rz, the inner membrane or i-spanin, has a largely alpha-helical periplasmic domain, whereas Rz1, the outer membrane or o-spanin, has a 25% proline content with no predicted secondary structure. We report that both Rz and Rz1 accumulate as homodimers covalently linked by intermolecular disulfide bonds involving all three Cys residues, two in Rz and one in Rz1. Moreover, of these three intermolecular disulfides, spanin function requires the presence of at least one of the two linkages nearest the Rz-Rz1 C-terminal interaction domains; i.e. either the Rz1-Rz1 disulfide or the distal Rz-Rz disulfide link. In a dsbC host, but not in dsbA or dsbA dsbC hosts, formation of the covalent homodimers of Rz is severely reduced and outer membrane disruption is significantly delayed, suggesting that the spanin pathway normally proceeds through DsbA-mediated formation of an intramolecular disulfide in Rz. In contrast, efficient formation of the Rz1-Rz1 disulfide requires DsbA. Finally, Dsb-independent formation of the covalent homodimer of either subunit requires the presence of the other, presumably as a template for close apposition of the thiols.
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Project description:Halogen bonding in ligand-protein complexes is currently widely exploited, e.g. in drug design or supramolecular chemistry. But little attention has been directed to other effects that may result from replacement of a hydrogen by a strongly electronegative halogen. Analysis of almost 30000 hydrogen bonds between protein and ligand demonstrates that the length of a hydrogen bond depends on the type of donor-acceptor pair. Interestingly, lengths of hydrogen bonds between a protein and a halogenated ligand are visibly shorter than those estimated for the same family of proteins in complexes with non-halogenated ligands. Taking into account the effect of halogenation on hydrogen bonding is thus important when evaluating structural and/or energetic parameters of ligand-protein complexes. All these observations are consistent with the concept that halogenation increases the acidity of the proximal amino/imino/hydroxyl groups and thus makes them better, i.e. stronger, H-bond donors.
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Project description:The tyrosine kinase, ζ-chain-associated protein of 70 kDa (ZAP70), is essential for T cell development and activation. However, it remains elusive whether a direct redox regulation affects ZAP70 activity upon TCR stimulation. Here, we showed that deficiency of non-selenocysteine containing phospholipid hydroperoxide glutathione peroxidase (NPGPx), a redox sensor, resulted in T cell hyperproliferation and elevated cytokine productions. Through proteomic approaches, ZAP70 is identified as the key interacting protein of NPGPx through disulfide bonding. Here we utilized the MS/MS spectra to identify the cysteine residues in ZAP70 for NPGPx-mediated regulation. Combined molecular approaches, our results elucidate a delicate redox mechanism that NPGPx serves as a modulator to curb ZAP70 functions in maintaining T cell homeostasis.
2021-01-25 | PXD017034 | Pride
Project description:BackgroundAllosteric disulfide bonds regulate protein function when they break and/or form. They typically have a -RHStaple configuration, which is defined by the sign of the five chi angles that make up the disulfide bond.ResultsAll disulfides in NMR and X-ray protein structures as well as in refined structure datasets were compared and contrasted for configuration and strain energy.ConclusionThe mean dihedral strain energy of 55,005 NMR structure disulfides was twice that of 42,690 X-ray structure disulfides. Moreover, the energies of all twenty types of disulfide bond was higher in NMR structures than X-ray structures, where there was an exponential decrease in the mean strain energy as the incidence of the disulfide type increased. Evaluation of protein structures for which there are X-ray and NMR models shows that the same disulfide bond can exist in different configurations in different models. A disulfide bond configuration that is rare in X-ray structures is the -LHStaple. In NMR structures, this disulfide is characterised by a particularly high potential energy and very short alpha-carbon distance. The HIV envelope glycoprotein gp120, for example, is regulated by thiol/disulfide exchange and contains allosteric -RHStaple bonds that can exist in the -LHStaple configuration. It is an open question which form of the disulfide is the functional configuration.
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Project description:Defensins are small proteins, usually ranging from 3 to 6 kDa, amphipathic, disulfide-rich, and with a small or even absent hydrophobic core. Since a hydrophobic core is generally found in globular proteins that fold in an aqueous solvent, the peculiar fold of defensins can challenge tertiary protein structure predictors. We performed a Protein Data Bank survey of small proteins (3-6 kDa) to understand the similarities of defensins with other small disulfide-rich proteins. We found no differences when we compared defensins with non-defensins regarding the proportion of apolar, polar and charged residues and their exposure to the solvent. Then we divided all small proteins (3-6 kDa) in the Protein Data Bank into two groups, one group with at least one disulfide bond (bonded, defensins included) and another group without any disulfide bond (unbonded). The group of bonded proteins contained apolar residues more exposed to the solvent than the unbonded group. The ab initio algorithm for tertiary protein structure prediction Robetta was more accurate at predicting unbonded than bonded proteins. On the other hand, the trRosetta algorithm, which uses artificial intelligence, improved the prediction of most bonded proteins, while for the unbonded group no improvement was obtained. Our work highlights one more layer of complexity for the prediction of protein tertiary structure: The ability of small disulfide-rich proteins to fold even with a poorly hydrophobic core.
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Project description:Disulfide bonds play an important role in protein folding and stability. However, the cross-linking of sites within proteins by cysteine disulfides has significant distance and dihedral angle constraints. Here we report the genetic encoding of noncanonical amino acids containing long side-chain thiols that are readily incorporated into both bacterial and mammalian proteins in good yields and with excellent fidelity. These amino acids can pair with cysteines to afford extended disulfide bonds and allow cross-linking of more distant sites and distinct domains of proteins. To demonstrate this notion, we preformed growth-based selection experiments at nonpermissive temperatures using a library of random ?-lactamase mutants containing these noncanonical amino acids. A mutant enzyme that is cross-linked by one such extended disulfide bond and is stabilized by ?9 °C was identified. This result indicates that an expanded set of building blocks beyond the canonical 20 amino acids can lead to proteins with improved properties by unique mechanisms, distinct from those possible through conventional mutagenesis schemes.
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Project description:Imatinib, one of the most used therapeutic agents to treat leukemia, is an inhibitor that specifically blocks the activity of tyrosine kinases. The molecule of imatinib is flexible and contains several functional groups able to take part in H-bonding and hydrophobic interactions. Analysis of molecular conformations for this drug was carried out using density functional theory calculations of rotation potentials along single bonds and by analyzing crystal structures of imatinib-containing compounds taken from the Cambridge Structural Database and the Protein Data Bank. Rotation along the N-C bond in the region of the amide group was found to be the reason for two relatively stable molecular conformations, an extended and a folded one. The role of various types of intermolecular interactions in stabilization of the particular molecular conformation was studied in terms of (i) the likelihood of H-bond formation, and (ii) their contribution to the Voronoi molecular surface. It is shown that experimentally observed hydrogen bonds are in accord with the likelihood of their formation. The number of H-bonds in ligand-receptor complexes surpasses that in imatinib salts due to the large number of donors and acceptors of H-bonding within the binding pocket of tyrosine kinases. Contribution of hydrophilic intermolecular interactions to the Voronoi molecular surface is similar for both conformations, while π...π stacking is more typical for the folded conformation of imatinib.
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