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Hydrophobic Contacts (hydrophobic + contact)
Selected AbstractsBuilding native protein conformation from NMR backbone chemical shifts using Monte Carlo fragment assemblyPROTEIN SCIENCE, Issue 8 2007Haipeng Gong Abstract We have been analyzing the extent to which protein secondary structure determines protein tertiary structure in simple protein folds. An earlier paper demonstrated that three-dimensional structure can be obtained successfully using only highly approximate backbone torsion angles for every residue. Here, the initial information is further diluted by introducing a realistic degree of experimental uncertainty into this process. In particular, we tackle the practical problem of determining three-dimensional structure solely from backbone chemical shifts, which can be measured directly by NMR and are known to be correlated with a protein's backbone torsion angles. Extending our previous algorithm to incorporate these experimentally determined data, clusters of structures compatible with the experimentally determined chemical shifts were generated by fragment assembly Monte Carlo. The cluster that corresponds to the native conformation was then identified based on four energy terms: steric clash, solvent-squeezing, hydrogen-bonding, and hydrophobic contact. Currently, the method has been applied successfully to five small proteins with simple topology. Although still under development, this approach offers promise for high-throughput NMR structure determination. [source] Amprenavir complexes with HIV-1 protease and its drug-resistant mutants altering hydrophobic clustersFEBS JOURNAL, Issue 18 2010Chen-Hsiang Shen The structural and kinetic effects of amprenavir (APV), a clinical HIV protease (PR) inhibitor, were analyzed with wild-type enzyme and mutants with single substitutions of V32I, I50V, I54V, I54M, I84V and L90M that are common in drug resistance. Crystal structures of the APV complexes at resolutions of 1.02,1.85 Å reveal the structural changes due to the mutations. Substitution of the larger side chains in PRV32I, PRI54M and PRL90M resulted in the formation of new hydrophobic contacts with flap residues, residues 79 and 80, and Asp25, respectively. Mutation to smaller side chains eliminated hydrophobic interactions in the PRI50V and PRI54V structures. The PRI84V,APV complex had lost hydrophobic contacts with APV, the PRV32I,APV complex showed increased hydrophobic contacts within the hydrophobic cluster and the PRI50V complex had weaker polar and hydrophobic interactions with APV. The observed structural changes in PRI84V,APV, PRV32I,APV and PRI50V,APV were related to their reduced inhibition by APV of six-, 10- and 30-fold, respectively, relative to wild-type PR. The APV complexes were compared with the corresponding saquinavir complexes. The PR dimers had distinct rearrangements of the flaps and 80,s loops that adapt to the different P1, groups of the inhibitors, while maintaining contacts within the hydrophobic cluster. These small changes in the loops and weak internal interactions produce the different patterns of resistant mutations for the two drugs. Structured digital abstract ,,MINT-7966480: HIV-1 PR (uniprotkb:P03366) and HIV-1 PR (uniprotkb:P03366) bind (MI:0407) by x-ray crystallography (MI:0114) [source] The capsid protein of human immunodeficiency virus: designing inhibitors of capsid assemblyFEBS JOURNAL, Issue 21 2009José L. Neira The mature capsid of human immunodeficiency virus, HIV-1, is formed by the assembly of copies of a capsid protein (CA). The C-terminal domain of CA, CTD, is able to homodimerize and most of the dimerization interface is formed by a single ,-helix from each monomer. Assembly of the HIV-1 capsid critically depends on CA,CA interactions, including CTD interaction with itself and with the CA N-terminal domain, NTD. This minireview reports on the search and the design of peptides and small organic compounds that are able to interact with the CTD and/or CA of HIV-1. Such molecules aim to disrupt and/or alter the oligomerization capability of CTD. The different peptides designed so far interact with CTD mainly via hydrophobic contacts with residues close or belonging to the interface between the dimerization helices. A CTD-binding organic compound also establishes hydrophobic contacts with regions involved in the interface between the NTD and CTD. These results open new venues for the development of new antiviral drugs that are able to interact with CA and/or its domains, hampering HIV-1 assembly and infection. [source] Structural characterization of Lyn-SH3 domain in complex with a herpesviral protein reveals an extended recognition motif that enhances binding affinityPROTEIN SCIENCE, Issue 10 2005Finn Bauer Abstract The Src homology 3 (SH3) domain of the Src family kinase Lyn binds to the herpesviral tyrosine kinase interacting protein (Tip) more than one order of magnitude stronger than other closely related members of the Src family. In order to identify the molecular basis for high-affinity binding, the structure of free and Tip-bound Lyn-SH3 was determined by NMR spectroscopy. Tip forms additional contacts outside its classical proline-rich recognition motif and, in particular, a strictly conserved leucine (L186) of the C-terminally adjacent sequence stretch packs into a hydrophobic pocket on the Lyn surface. Although the existence of this pocket is no unique property of Lyn-SH3, Lyn is the only Src family kinase that contains an additional aromatic residue (H41) in the n-Src loop as part of this pocket. H41 covers L186 of Tip by forming tight hydrophobic contacts, and model calculations suggest that the increase in binding affinity compared with other SH3 domains can mainly be attributed to these additional interactions. These findings indicate that this pocket can mediate specificity even between otherwise closely related SH3 domains. [source] Crystal structures of oxidized and reduced forms of human mitochondrial thioredoxin 2PROTEIN SCIENCE, Issue 10 2005Aude Smeets ASK1, apoptosis signal-regulating kinase 1; TXN, thioredoxin; hTXN1, human cytosolic/nuclear thioredoxin 1; hTXN2, human mitochondrial thioredoxin 2; hPRDX5, human peroxiredoxin 5. Gene symbols in this article follow standard nomenclature defined by the Human Genome Organization Nomenclature Committee (http://www.gene.ucl.ac.uk/nomenclature/). For this reason TXN is used instead of the commonly used Trx for designating thioredoxin in the literature. Abstract Mammalian thioredoxin 2 is a mitochondrial isoform of highly evolutionary conserved thioredoxins. Thioredoxins are small ubiquitous protein,disulfide oxidoreductases implicated in a large variety of biological functions. In mammals, thioredoxin 2 is encoded by a nuclear gene and is targeted to mitochondria by a N-terminal mitochondrial presequence. Recently, mitochondrial thioredoxin 2 was shown to interact with components of the mitochondrial respiratory chain and to play a role in the control of mitochondrial membrane potential, regulating mitochondrial apoptosis signaling pathway. Here we report the first crystal structures of a mammalian mitochondrial thioredoxin 2. Crystal forms of reduced and oxidized human thioredoxin 2 are described at 2.0 and 1.8 Å resolution. Though the folding is rather similar to that of human cytosolic/nuclear thioredoxin 1, important differences are observed during the transition between the oxidized and the reduced states of human thioredoxin 2, compared with human thioredoxin 1. In spite of the absence of the Cys residue implicated in dimer formation in human thioredoxin 1, dimerization still occurs in the crystal structure of human thioredoxin 2, mainly mediated by hydrophobic contacts, and the dimers are associated to form two-dimensional polymers. Interestingly, the structure of human thioredoxin 2 reveals possible interaction domains with human peroxiredoxin 5, a substrate protein of human thioredoxin 2 in mitochondria. [source] Self-association of an amphipathic helix peptide inhibitor of HIV-1 integrase assessed by electro spray ionization mass spectrometry in trifluoroethanol/water mixturesRAPID COMMUNICATIONS IN MASS SPECTROMETRY, Issue 5 2001S. Fermandjian Establishing the auto-associative properties of a molecule in solution can be important for determination of its structure and function. EAA26 (VESMNEELKKIIAQVRAQAEHLKTAY) has been designed to inhibit HIV-1 integrase via formation of a stable coiled-coil structure with a nearly homologous segment in the enzyme. The latter catalyzes the permanent incorporation of a DNA copy of the retrovirus genome into host cell DNA, and is thus essential to the life of the retrovirus. This makes integrase an obvious drug target in the therapy of AIDS. The present work has demonstrated, using electrospray ionization mass spectrometry (ESI-MS), that EAA26 is monomeric in pure water, and tetrameric and dimeric at respectively low and medium concentrations of 2,2,2-trifluoroethanol (TFE), and again monomeric at higher TFE concentrations. Thus, the apolar solvent TFE may contribute to either stabilization or disruption of the intermolecular hydrophobic contacts depending on its concentration in aqueous solution. Previous NMR and ultracentifugation results are thus confirmed, indicating the reliability of ESI-MS for defining the self-association state of biologically relevant peptides in both water and organic-water solutions. Copyright © 2001 John Wiley & Sons, Ltd. [source] Analysis of quinazoline and pyrido[2,3- d]pyrimidine N9,C10 reversed-bridge antifolates in complex with NADP+ and Pneumocystis carinii dihydrofolate reductaseACTA CRYSTALLOGRAPHICA SECTION D, Issue 9 2002Vivian Cody Structural studies of two ternary complexes of Pneumocystis carinii dihydrofolate reductase (pcDHFR) with the cofactor NADP+ and potent antifolates, the N9,C10 reversed-bridge inhibitor 2,4-diamino-6-[N -(2,,5,-dimethoxybenzyl)- N -methylamino]quinazoline (1) and its 3,,5,-dimethoxypyrido[2,3- d]pyrimidine analog (2), were carried out. Data for the monoclinic crystals were refined to 1.90,Å resolution for the complex with (1) (R = 0.178) and to 2.1,Å resolution for the complex with (2) (R = 0.193). The effect of the N9,C10 reversed-bridge geometry is to distort the bridge from coplanarity with the pyrido[2,3- d]pyrimidine or quinazoline ring system and to twist the C10 methylene conformation toward a gauche conformation. This change also influences the conformation of the methoxybenzyl ring, moving it away from a trans position. This change places the 5,-methoxy group deeper within the hydrophobic pocket made by Ile65, Pro66 and Phe69 of the pcDHFR active site. These results also revealed the first observation of an unusual conformation for the reversed-bridge geometry (C5,C6,N9,C10 torsion angle) in antifolate (2). The electron density is consistent with the presence of two models (conformers 2-1 and 2-2) that result from inversion of the geometry at N9. The four examples of N9,C10 reversed-bridge antifolates cluster in two conformations, with the structure of quinazoline (1) similar to that previously reported for its 2,,5,-dimethoxypyrido[2,3- d]pyrimidine analog (3). The two conformers of (2) differ from these and each other by a twisted-bridge geometry that results in the dimethoxybenzyl ring occupying the same conformational space. Conformer 2-2 also has the N9,C10 reversed bridge perpendicular to the pyrido[2,3- d]pyrimidine plane, in contrast to the gauche,trans conformation normally observed. As a result of these changes, the N9 methyl probes conformational space in the active site not normally occupied by antifolate structures. The N9 methyl of conformer 2-2 makes close contacts to the conserved Leu25 as well as the hydroxyl O atoms of the nicotinamide ribose and Ser64, whereas the other three reversed-bridge conformers make weak hydrophobic contacts with Ile123, Thr61 and Ile65. These antifolates are ten times more selective for pcDHFR than the C9,N10 bridge parent trimetrexate. However, pyrido[2,3- d]pyrimidines (2) and (3) are three times more selective for pcDHFR than quinazoline (1) is for rat liver DHFR. These data suggest that the loss of hydrogen-bonding interactions with N8 is more important to potency than the interactions of the methoxybenzyl substituents. [source] A High Performance Theory for Thermodynamic Study on the Binding of Human Serum Albumin with Erbium ChlorideCHINESE JOURNAL OF CHEMISTRY, Issue 2 2009G. Rezaei BEHBEHANI Abstract A thermodynamic study of the interaction between erbium(III) chloride (Er3+) and human serum albumin (HSA) was studied at pH=7.0, 27 and 37 °C in phosphate buffer by isothermal titration calorimetry (ITC). The present study reports the thermodynamic parameters that govern HSA-Er3+ interactions. The extended solvation theory was used to reproduce the enthalpies of HSA-Er3+ interactions over the whole range of Er3+ concentrations. The binding parameters recovered from the new model were attributed to the structural change of HSA and its biological activity. The results obtained indicate that there is a set of two identical binding sites for Er3+ ions with negative cooperativity. The enhancement of complex formation by Er3+ and concomitant increase in ?S suggest that the metal ion plays a role in increasing the number of hydrophobic contacts. The binding parameters discovered from the extended solvation model indicate that the stability of HSA molecule is increased as a result of its interaction with Er3+ ions. [source] | ||||||||||