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Article ; Online: The pan-RAF-MEK non degrading molecular glue NST-628 is a potent and brain penetrant inhibitor of the RAS-MAPK pathway with activity across diverse RAS- and RAF-driven cancers.

Ryan, Meagan B / Quade, Bradley / Schenk, Natasha / Fang, Zhong / Zingg, Marshall / Cohen, Steven E / Swalm, Brooke M / Li, Chun / Ozen, Aysegul / Ye, Chaoyang / Ritorto, Maria Stella / Huang, Xin / Dar, Arvin C / Han, Yongxin / Hoeflich, Klaus P / Hale, Michael / Hagel, Margit

Cancer discovery

2024

Abstract: Alterations in the RAS-MAPK signaling cascade are common across multiple solid tumor types and is a driver for many cancers. NST-628 is a potent pan-RAF-MEK molecular glue that prevents phosphorylation and activation of MEK by RAF, overcoming the ... ...

Abstract	Alterations in the RAS-MAPK signaling cascade are common across multiple solid tumor types and is a driver for many cancers. NST-628 is a potent pan-RAF-MEK molecular glue that prevents phosphorylation and activation of MEK by RAF, overcoming the limitations of traditional RAS-MAPK inhibitors and leading to deep durable inhibition of the pathway. Cellular, biochemical, and structural analysis of RAF-MEK complexes show that NST-628 engages all isoforms of RAFand prevents the formation of BRAF-CRAF heterodimers, a differentiated mechanism from all current RAF inhibitors. With a potent and durable inhibition of the RAF-MEK signaling complex as well as high intrinsic permeability into the brain, NST-628 demonstrates broad efficacy in cellular and patient-derived tumor models harboring diverse MAPK pathway alterations, including orthotopic intracranial models. Given its functional and pharmacokinetic mechanisms that are differentiated from previous therapies , NST-628 is positioned to make an impact clinically in an areas of unmet patient need.
Language	English
Publishing date	2024-04-08
Publishing country	United States
Document type	Journal Article
ZDB-ID	2625242-9
ISSN	2159-8290 ; 2159-8274
ISSN (online)	2159-8290
ISSN	2159-8274
DOI	10.1158/2159-8290.CD-24-0139
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Article ; Online: Resistance outside the substrate envelope: hepatitis C NS3/4A protease inhibitors.

Özen, Ayşegül / Prachanronarong, Kristina / Matthew, Ashley N / Soumana, Djade I / Schiffer, Celia A

Critical reviews in biochemistry and molecular biology

2019 Volume 54, Issue 1, Page(s) 11–26

Abstract: Direct acting antivirals have dramatically increased the efficacy and tolerability of hepatitis C treatment, but drug resistance has emerged with some of these inhibitors, including nonstructural protein 3/4 A protease inhibitors (PIs). Although many co- ... ...

Abstract	Direct acting antivirals have dramatically increased the efficacy and tolerability of hepatitis C treatment, but drug resistance has emerged with some of these inhibitors, including nonstructural protein 3/4 A protease inhibitors (PIs). Although many co-crystal structures of PIs with the NS3/4A protease have been reported, a systematic review of these crystal structures in the context of the rapidly emerging drug resistance especially for early PIs has not been performed. To provide a framework for designing better inhibitors with higher barriers to resistance, we performed a quantitative structural analysis using co-crystal structures and models of HCV NS3/4A protease in complex with natural substrates and inhibitors. By comparing substrate structural motifs and active site interactions with inhibitor recognition, we observed that the selection of drug resistance mutations correlates with how inhibitors deviate from viral substrates in molecular recognition. Based on this observation, we conclude that guiding the design process with native substrate recognition features is likely to lead to more robust small molecule inhibitors with decreased susceptibility to resistance.
MeSH term(s)	Animals ; Catalytic Domain/drug effects ; Drug Resistance, Viral ; Hepacivirus/drug effects ; Hepacivirus/metabolism ; Hepatitis C/drug therapy ; Hepatitis C/virology ; Humans ; Protease Inhibitors/chemistry ; Protease Inhibitors/pharmacology ; Protein Conformation/drug effects ; Serine Proteases/chemistry ; Serine Proteases/metabolism ; Viral Nonstructural Proteins/antagonists & inhibitors ; Viral Nonstructural Proteins/chemistry ; Viral Nonstructural Proteins/metabolism
Chemical Substances	Protease Inhibitors ; Viral Nonstructural Proteins ; NS3-4A serine protease, Hepatitis C virus (EC 3.4.-) ; Serine Proteases (EC 3.4.-)
Language	English
Publishing date	2019-03-01
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	1000977-2
ISSN	1549-7798 ; 1381-3455 ; 1040-9238
ISSN (online)	1549-7798
ISSN	1381-3455 ; 1040-9238
DOI	10.1080/10409238.2019.1568962
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Zs.A 1024: Show issues

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Article ; Online: Improving the Resistance Profile of Hepatitis C NS3/4A Inhibitors: Dynamic Substrate Envelope Guided Design.

Ozen, Ayşegül / Sherman, Woody / Schiffer, Celia A

Journal of chemical theory and computation

2014 Volume 9, Issue 12, Page(s) 5693–5705

Abstract: Drug resistance is a principal concern in the treatment of quickly evolving diseases. The viral protease NS3/4A is a primary drug target for the hepatitis C virus (HCV) and is known to evolve resistance mutations in response to drug therapy. At the ... ...

Abstract	Drug resistance is a principal concern in the treatment of quickly evolving diseases. The viral protease NS3/4A is a primary drug target for the hepatitis C virus (HCV) and is known to evolve resistance mutations in response to drug therapy. At the molecular level, drug resistance reflects a subtle change in the balance of molecular recognition by NS3/4A; the drug resistant protease variants are no longer effectively inhibited by the competitive active site inhibitors but can still process the natural substrates with enough efficiency for viral survival. In previous works we have developed the "substrate envelope" hypothesis, which posits that inhibitors should be less susceptible to drug resistance if they better mimic the natural substrate molecular recognition features. In this work, we perform molecular dynamics simulations on four native substrates bound to NS3/4A and discover a clearly conserved dynamic substrate envelope. We show that the most severe drug resistance mutations in NS3/4A occur at residues that are outside the substrate envelope. Comparative analysis of three NS3/4A inhibitors reveals structural and dynamic characteristics of inhibitors that could lead to resistance. We also suggest inhibitor modifications to improve resistance profiles based on the dynamic substrate envelope. This study provides a general framework for guiding the development of novel inhibitors that will be more robust against resistance by mimicking the static and dynamic binding characteristics of natural substrates.
Language	English
Publishing date	2014-01-23
Publishing country	United States
Document type	Journal Article
ISSN	1549-9626
ISSN (online)	1549-9626
DOI	10.1021/ct400603p
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Article: Drug-resistant HIV-1 protease regains functional dynamics through cleavage site coevolution.

Özer, Nevra / Özen, Ayşegül / Schiffer, Celia A / Haliloğlu, Türkan

Evolutionary applications

2015 Volume 8, Issue 2, Page(s) 185–198

Abstract: Drug resistance is caused by mutations that change the balance of recognition favoring substrate cleavage over inhibitor binding. Here, a structural dynamics perspective of the regained wild-type functioning in mutant HIV-1 proteases with coevolution of ... ...

Abstract	Drug resistance is caused by mutations that change the balance of recognition favoring substrate cleavage over inhibitor binding. Here, a structural dynamics perspective of the regained wild-type functioning in mutant HIV-1 proteases with coevolution of the natural substrates is provided. The collective dynamics of mutant structures of the protease bound to p1-p6 and NC-p1 substrates are assessed using the Anisotropic Network Model (ANM). The drug-induced protease mutations perturb the mechanistically crucial hinge axes that involve key sites for substrate binding and dimerization and mainly coordinate the intrinsic dynamics. Yet with substrate coevolution, while the wild-type dynamic behavior is restored in both p1-p6 ((LP) (1'F)p1-p6D30N/N88D) and NC-p1 ((AP) (2) (V)NC-p1V82A) bound proteases, the dynamic behavior of the NC-p1 bound protease variants (NC-p1V82A and (AP) (2) (V)NC-p1V82A) rather resemble those of the proteases bound to the other substrates, which is consistent with experimental studies. The orientational variations of residue fluctuations along the hinge axes in mutant structures justify the existence of coevolution in p1-p6 and NC-p1 substrates, that is, the dynamic behavior of hinge residues should contribute to the interdependent nature of substrate recognition. Overall, this study aids in the understanding of the structural dynamics basis of drug resistance and evolutionary optimization in the HIV-1 protease system.
Language	English
Publishing date	2015-01-11
Publishing country	England
Document type	Journal Article
ZDB-ID	2405496-3
ISSN	1752-4563 ; 1752-4571
ISSN (online)	1752-4563
ISSN	1752-4571
DOI	10.1111/eva.12241
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Article ; Online: HIV-1 Protease and Substrate Coevolution Validates the Substrate Envelope As the Substrate Recognition Pattern.

Ozen, Ayşegül / Haliloğlu, Türkan / Schiffer, Celia A

Journal of chemical theory and computation

2013 Volume 8, Issue 2

Abstract: Drug resistance of HIV-1 protease alters the balance in the molecular recognition events in favor of substrate processing versus inhibitor binding. To develop robust inhibitors targeting ensembles of drug-resistant variants, the code of this balance ... ...

Abstract	Drug resistance of HIV-1 protease alters the balance in the molecular recognition events in favor of substrate processing versus inhibitor binding. To develop robust inhibitors targeting ensembles of drug-resistant variants, the code of this balance needs to be cracked. For this purpose, the principles governing the substrate recognition are required to be revealed. Previous crystallographic studies on the WT protease-substrate complexes showed that the substrates have a conserved consensus volume in the protease active site despite their low sequence homology. This consensus volume is termed as the substrate envelope. The substrate envelope was recently reevaluated by taking the substrate dynamics into account, and the dynamic substrate envelope was reported to better define the substrate specificity for HIV-1 protease. Drug resistance occurs mostly through mutations in the protease, occasionally accompanied by cleavage site mutations. In this study, three coevolved protease-substrate complexes (
Language	English
Publishing date	2013-12-03
Publishing country	United States
Document type	Journal Article
ISSN	1549-9626
ISSN (online)	1549-9626
DOI	10.1021/ct200668a
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Article ; Online: Selectively Modulating Conformational States of USP7 Catalytic Domain for Activation.

Özen, Ayşegül / Rougé, Lionel / Bashore, Charlene / Hearn, Brian R / Skelton, Nicholas J / Dueber, Erin C

Structure (London, England : 1993)

2017 Volume 26, Issue 1, Page(s) 72–84.e7

Abstract: Ubiquitin-specific protease 7 (USP7) deubiquitinase activity is controlled by a number of regulatory factors, including stimulation by intramolecular accessory domains. Alone, the USP7 catalytic domain (USP7cd) shows limited activity and apo USP7cd ... ...

Abstract	Ubiquitin-specific protease 7 (USP7) deubiquitinase activity is controlled by a number of regulatory factors, including stimulation by intramolecular accessory domains. Alone, the USP7 catalytic domain (USP7cd) shows limited activity and apo USP7cd crystal structures reveal a disrupted catalytic triad. By contrast, ubiquitin-conjugated USP7cd structures demonstrate the canonical cysteine protease active-site geometry; however, the structural features of the USP7cd that stabilize the inactive conformation and the mechanism of transition between inactive and active states remain unclear. Here we use comparative structural analyses, molecular dynamics simulations, and in silico sequence re-engineering via directed sampling by RosettaDesign to identify key molecular determinants of USP7cd activation and successfully engineer USP7cd for improved activity. Full kinetic analysis and multiple X-ray crystal structures of our designs indicate that electrostatic interactions in the distal "switching loop" region and local packing in the hydrophobic core mediate subtle but significant conformational changes that modulate USP7cd activation.
MeSH term(s)	Amino Acid Sequence ; Amino Acid Substitution ; Catalytic Domain ; Cloning, Molecular ; Crystallography, X-Ray ; Enzyme Activation ; Enzyme Inhibitors/chemical synthesis ; Enzyme Inhibitors/chemistry ; Escherichia coli/genetics ; Escherichia coli/metabolism ; Gene Expression ; Genetic Vectors/chemistry ; Genetic Vectors/metabolism ; Humans ; Hydrophobic and Hydrophilic Interactions ; Kinetics ; Molecular Dynamics Simulation ; Mutation ; Peptidomimetics/chemical synthesis ; Peptidomimetics/chemistry ; Protein Binding ; Protein Conformation, alpha-Helical ; Protein Conformation, beta-Strand ; Protein Interaction Domains and Motifs ; Recombinant Proteins/chemistry ; Recombinant Proteins/genetics ; Recombinant Proteins/metabolism ; Static Electricity ; Substrate Specificity ; Thermodynamics ; Ubiquitin-Specific Peptidase 7/antagonists & inhibitors ; Ubiquitin-Specific Peptidase 7/chemistry ; Ubiquitin-Specific Peptidase 7/genetics ; Ubiquitin-Specific Peptidase 7/metabolism
Chemical Substances	Enzyme Inhibitors ; Peptidomimetics ; Recombinant Proteins ; USP7 protein, human (EC 3.4.19.12) ; Ubiquitin-Specific Peptidase 7 (EC 3.4.19.12)
Language	English
Publishing date	2017-12-14
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1213087-4
ISSN	1878-4186 ; 0969-2126
ISSN (online)	1878-4186
ISSN	0969-2126
DOI	10.1016/j.str.2017.11.010
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Zs.A 4141: Show issues

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Article ; Online: HIV-1 protease-substrate coevolution in nelfinavir resistance.

Kolli, Madhavi / Ozen, Ayşegül / Kurt-Yilmaz, Nese / Schiffer, Celia A

Journal of virology

2014 Volume 88, Issue 13, Page(s) 7145–7154

Abstract: Unlabelled: Resistance to various human immunodeficiency virus type 1 (HIV-1) protease inhibitors (PIs) challenges the effectiveness of therapies in treating HIV-1-infected individuals and AIDS patients. The virus accumulates mutations within the ... ...

Abstract	Unlabelled: Resistance to various human immunodeficiency virus type 1 (HIV-1) protease inhibitors (PIs) challenges the effectiveness of therapies in treating HIV-1-infected individuals and AIDS patients. The virus accumulates mutations within the protease (PR) that render the PIs less potent. Occasionally, Gag sequences also coevolve with mutations at PR cleavage sites contributing to drug resistance. In this study, we investigated the structural basis of coevolution of the p1-p6 cleavage site with the nelfinavir (NFV) resistance D30N/N88D protease mutations by determining crystal structures of wild-type and NFV-resistant HIV-1 protease in complex with p1-p6 substrate peptide variants with L449F and/or S451N. Alterations of residue 30's interaction with the substrate are compensated by the coevolving L449F and S451N cleavage site mutations. This interdependency in the PR-p1-p6 interactions enhances intermolecular contacts and reinforces the overall fit of the substrate within the substrate envelope, likely enabling coevolution to sustain substrate recognition and cleavage in the presence of PR resistance mutations. Importance: Resistance to human immunodeficiency virus type 1 (HIV-1) protease inhibitors challenges the effectiveness of therapies in treating HIV-1-infected individuals and AIDS patients. Mutations in HIV-1 protease selected under the pressure of protease inhibitors render the inhibitors less potent. Occasionally, Gag sequences also mutate and coevolve with protease, contributing to maintenance of viral fitness and to drug resistance. In this study, we investigated the structural basis of coevolution at the Gag p1-p6 cleavage site with the nelfinavir (NFV) resistance D30N/N88D protease mutations. Our structural analysis reveals the interdependency of protease-substrate interactions and how coevolution may restore substrate recognition and cleavage in the presence of protease drug resistance mutations.
MeSH term(s)	Crystallography, X-Ray ; Drug Resistance, Viral ; Evolution, Molecular ; HIV Infections/drug therapy ; HIV Infections/enzymology ; HIV Infections/virology ; HIV Protease/chemistry ; HIV Protease/genetics ; HIV Protease/metabolism ; HIV Protease Inhibitors/pharmacology ; HIV-1/drug effects ; HIV-1/enzymology ; Humans ; Models, Molecular ; Nelfinavir/pharmacology ; Peptide Fragments ; Protein Conformation ; Substrate Specificity ; gag Gene Products, Human Immunodeficiency Virus/chemistry ; gag Gene Products, Human Immunodeficiency Virus/genetics ; gag Gene Products, Human Immunodeficiency Virus/metabolism
Chemical Substances	HIV Protease Inhibitors ; Peptide Fragments ; gag Gene Products, Human Immunodeficiency Virus ; gag protein p1, Human immunodeficiency virus ; p6 gag protein, Human immunodeficiency virus 1 ; HIV Protease (EC 3.4.23.-) ; Nelfinavir (HO3OGH5D7I)
Language	English
Publishing date	2014-04-09
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	80174-4
ISSN	1098-5514 ; 0022-538X
ISSN (online)	1098-5514
ISSN	0022-538X
DOI	10.1128/JVI.00266-14
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Zs.A 609: Show issues

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Article ; Online: Structural basis and distal effects of Gag substrate coevolution in drug resistance to HIV-1 protease.

Özen, Ayşegül / Lin, Kuan-Hung / Kurt Yilmaz, Nese / Schiffer, Celia A

Proceedings of the National Academy of Sciences of the United States of America

2014 Volume 111, Issue 45, Page(s) 15993–15998

Abstract: Drug resistance mutations in response to HIV-1 protease inhibitors are selected not only in the drug target but elsewhere in the viral genome, especially at the protease cleavage sites in the precursor protein Gag. To understand the molecular basis of ... ...

Abstract	Drug resistance mutations in response to HIV-1 protease inhibitors are selected not only in the drug target but elsewhere in the viral genome, especially at the protease cleavage sites in the precursor protein Gag. To understand the molecular basis of this protease-substrate coevolution, we solved the crystal structures of drug resistant I50V/A71V HIV-1 protease with p1-p6 substrates bearing coevolved mutations. Analyses of the protease-substrate interactions reveal that compensatory coevolved mutations in the substrate do not restore interactions lost due to protease mutations, but instead establish other interactions that are not restricted to the site of mutation. Mutation of a substrate residue has distal effects on other residues' interactions as well, including through the induction of a conformational change in the protease. Additionally, molecular dynamics simulations suggest that restoration of active site dynamics is an additional constraint in the selection of coevolved mutations. Hence, protease-substrate coevolution permits mutational, structural, and dynamic changes via molecular mechanisms that involve distal effects contributing to drug resistance.
MeSH term(s)	Amino Acid Substitution ; Crystallography, X-Ray ; Drug Resistance, Viral/genetics ; Evolution, Molecular ; HIV Protease/genetics ; HIV Protease/metabolism ; HIV-1/genetics ; HIV-1/metabolism ; Humans ; Mutation, Missense ; gag Gene Products, Human Immunodeficiency Virus/genetics ; gag Gene Products, Human Immunodeficiency Virus/metabolism
Chemical Substances	gag Gene Products, Human Immunodeficiency Virus ; HIV Protease (EC 3.4.23.-) ; p16 protease, Human immunodeficiency virus 1 (EC 3.4.23.-)
Language	English
Publishing date	2014-10-29
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	209104-5
ISSN	1091-6490 ; 0027-8424
ISSN (online)	1091-6490
ISSN	0027-8424
DOI	10.1073/pnas.1414063111
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Zs.A 1148: Show issues

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Article ; Online: Machine learning integration for predicting the effect of single amino acid substitutions on protein stability

Haliloğlu Türkan / Alpaydın Ethem / Gönen Mehmet / Özen Ayşegül

BMC Structural Biology, Vol 9, Iss 1, p

2009 Volume 66

Abstract: Abstract Background Computational prediction of protein stability change due to single-site amino acid substitutions is of interest in protein design and analysis. We consider the following four ways to improve the performance of the currently available ... ...

Abstract	Abstract Background Computational prediction of protein stability change due to single-site amino acid substitutions is of interest in protein design and analysis. We consider the following four ways to improve the performance of the currently available predictors: (1) We include additional sequence- and structure-based features, namely, the amino acid substitution likelihoods, the equilibrium fluctuations of the alpha- and beta-carbon atoms, and the packing density. (2) By implementing different machine learning integration approaches, we combine information from different features or representations. (3) We compare classification vs. regression methods to predict the sign vs. the output of stability change. (4) We allow a reject option for doubtful cases where the risk of misclassification is high. Results We investigate three different approaches: early, intermediate and late integration, which respectively combine features, kernels over feature subsets, and decisions. We perform simulations on two data sets: (1) S1615 is used in previous studies, (2) S2783 is the updated version (as of July 2, 2009) extracted also from ProTherm. For S1615 data set, our highest accuracy using both sequence and structure information is 0.842 on cross-validation and 0.904 on testing using early integration. Newly added features, namely, local compositional packing and the mobility extent of the mutated residues, improve accuracy significantly with intermediate integration. For S2783 data set, we also train regression methods to estimate not only the sign but also the amount of stability change and apply risk-based classification to reject when the learner has low confidence and the loss of misclassification is high. The highest accuracy is 0.835 on cross-validation and 0.832 on testing using only sequence information. The percentage of false positives can be decreased to less than 0.005 by rejecting 10 per cent using late integration. Conclusion We find that in both early and late integration, combining inputs or decisions is useful in increasing accuracy. Intermediate integration allows assessing the contributions of individual features by looking at the assigned weights. Overall accuracy of regression is not better than that of classification but it has less false positives, especially when combined with the reject option. The server for stability prediction for three integration approaches and the data sets are available at http://www.prc.boun.edu.tr/appserv/prc/mlsta .
Keywords	Biology (General) ; QH301-705.5
Subject code	004
Language	English
Publishing date	2009-10-01T00:00:00Z
Publisher	BioMed Central
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article: Dynamics of Preferential Substrate Recognition in HIV-1 Protease: Redefining the Substrate Envelope

Özen, Ayşegül / Haliloğlu, Türkan / Schiffer, Celia A

Journal of molecular biology. 2011 July 22, v. 410, no. 4

2011

Abstract: Human immunodeficiency virus type 1 (HIV-1) protease (PR) permits viral maturation by processing the gag and gag-pro-pol polyproteins. HIV-1 PR inhibitors (PIs) are used in combination antiviral therapy but the emergence of drug resistance has limited ... ...

Abstract	Human immunodeficiency virus type 1 (HIV-1) protease (PR) permits viral maturation by processing the gag and gag-pro-pol polyproteins. HIV-1 PR inhibitors (PIs) are used in combination antiviral therapy but the emergence of drug resistance has limited their efficacy. The rapid evolution of HIV-1 necessitates consideration of drug resistance in novel drug design. Drug-resistant HIV-1 PR variants no longer inhibited efficiently, continue to hydrolyze the natural viral substrates. Though highly diverse in sequence, the HIV-1 PR substrates bind in a conserved three-dimensional shape we termed the substrate envelope. Earlier, we showed that resistance mutations arise where PIs protrude beyond the substrate envelope, because these regions are crucial for drug binding but not for substrate recognition. We extend this model by considering the role of protein dynamics in the interaction of HIV-1 PR with its substrates. We simulated the molecular dynamics of seven PR-substrate complexes to estimate the conformational flexibility of the bound substrates. Interdependence of substrate–protease interactions might compensate for variations in cleavage-site sequences and explain how a diverse set of sequences are recognized as substrates by the same enzyme. This diversity might be essential for regulating sequential processing of substrates. We define a dynamic substrate envelope as a more accurate representation of PR–substrate interactions. This dynamic substrate envelope, described by a probability distribution function, is a powerful tool for drug design efforts targeting ensembles of resistant HIV-1 PR variants with the aim of developing drugs that are less susceptible to resistance.
Keywords	Human immunodeficiency virus 1 ; drug resistance ; drugs ; evolution ; models ; molecular dynamics ; mutation ; probability distribution ; proteinases ; therapeutics
Language	English
Dates of publication	2011-0722
Size	p. 726-744.
Publishing place	Elsevier Ltd
Document type	Article
ZDB-ID	80229-3
ISSN	1089-8638 ; 0022-2836
ISSN (online)	1089-8638
ISSN	0022-2836
DOI	10.1016/j.jmb.2011.03.053
Database	NAL-Catalogue (AGRICOLA)

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