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Small Molecule Regulation of Protein Conformation by Binding in the Flap of HIV Protease

Theresa Tiefenbrunn, Stefano Forli, Michael M. Baksh, Max W. Chang, Meaghan Happer, Ying-Chuan Lin, Alexander L. Perryman, Jin-Kyu Rhee, Bruce E. Torbett, Arthur J. Olson, John H. Elder, M. G. Finn (+1 others)
2013 ACS Chemical Biology  
In solution, 1F1 and 1F1-N raise the Tm of apo-PR by 3.5-5 °C as assayed by differential scanning fluorimetry (DSF) and show equivalent low-micromolar binding constants to both apo-PR and pepstatin:PR,  ...  The fragment indole-6-carboxylic acid (1F1), previously identified as a flap site binder in a fragment-based screen against HIV protease (PR), has been cocrystallized with pepstatin-inhibited PR and with  ...  Figure 5 . 5 Differential scanning fluorimetry of apo, autolysis resistant HIV PR in the presence and absence of fragments showing that 1F1 and 1F1-N stabilize the protease in solution, consistent with  ... 
doi:10.1021/cb300611p pmid:23540839 pmcid:PMC3769432 fatcat:4j5kzia3vvf3jeistq2yv7brx4

Molecular Structure and Biochemical Properties of the HCCH−Zn2+Site in HIV-1 Vif

Kalyan Giri, Robert A. Scott, Ernest L. Maynard
2009 Biochemistry  
We have employed the biomimetic peptide HCCHp (HIV-1 Vif amino acids 101-142) in order to determine the zinc ligands and investigate the role of zinc binding in Cul5 recognition.  ...  HIV-1 accessory proteins modulate the host cellular environment to permit viral replication and transmission (reviewed in (1-4) ).  ...  ACKNOWLEDGMENT We greatly appreciate the human cul5 clone, which was a gift from Dr. Joan W. Conaway (Stowers Institute for Medical Research, Kansas City, Missouri 64110).  ... 
doi:10.1021/bi900677w pmid:19588889 pmcid:PMC2729716 fatcat:pbzm3sdtjbhitbqtkc3nuc4xiu

A mimic of HIV-1 nucleocapsid protein impairs reverse transcription and displays antiviral activity

S. Druillennec, C. Z. Dong, S. Escaich, N. Gresh, A. Bousseau, B. P. Roques, M. C. Fournie-Zaluski
1999 Proceedings of the National Academy of Sciences of the United States of America  
Combined inhibition of HIV-1 reverse transcriptase and protease has significantly improved the treatment of AIDS.  ...  In vitro, RB 2121 does not interfere with HIV-1 cell entry and viral enzymes but is able to inhibit the annealing activities of NCp7 by recognizing nucleic acids.  ...  Meudal and P. Petitjean for NMR studies and peptide synthesis, J. F. Ferron and M. F. Bachelot for their contribution in biochemical studies, and H. de Rocquigny for helpful discussions.  ... 
doi:10.1073/pnas.96.9.4886 pmid:10220388 pmcid:PMC21786 fatcat:jcjecddbdbclph65jtwiwbh7cq

Are weak protein–protein interactions the general rule in capsid assembly?

Adam Zlotnick
2003 Virology  
Acknowledgments Development of models of virus assembly and the role of nucleic acid in assembly were supported by grants from the American Cancer Society (RSG-99-339-04-MBC) and the National Science Foundation  ...  In the presence of zinc, the site size was 8 nucleotides. In the absence of zinc, it was 11 nucleotides, suggesting that zinc induced a more compact conformation for NC.  ...  protein (which has a cone-shaped quaternary structure in mature HIV), and the nucleocapsid (NC) protein, which binds RNA in part through two zinc fingers.  ... 
doi:10.1016/s0042-6822(03)00586-5 pmid:14585329 fatcat:kz557iconnd5pph6d65q7tby4e

1.92 Angstrom Zinc-Free APOBEC3F Catalytic Domain Crystal Structure

Nadine M. Shaban, Ke Shi, Ming Li, Hideki Aihara, Reuben S. Harris
2016 Journal of Molecular Biology  
The APOBEC3 family of DNA cytosine deaminases is capable of restricting the replication of HIV-1 and other pathogens.  ...  We show that the enzyme is active in the presence of zinc and cobalt, but not with other divalent metals.  ...  Acknowledgments The Harris lab is supported by NIH NIAID AI064046, NIGMS GM091743, and HHMI. The Aihara lab is supported by NIH NIGMS grants GM095558 and GM109770.  ... 
doi:10.1016/j.jmb.2016.04.026 pmid:27139641 pmcid:PMC5142242 fatcat:e4oiudmn6vgfpe2zoc7djgfh4e

Resistance from Afar: Distal Mutation V36M Allosterically Modulates the Active Site to Accentuate Drug Resistance in HCV NS3/4A Protease [article]

Aysegul Ozen, Kuan-Hung Lin, Keith P Romano, Davide Tavella, Alicia Newton, Christos J Petropoulos, Wei Huang, Cihan Aydin, Celia Schiffer
2018 biorxiv/medrxiv   pre-print
In this study the mechanism by which V36M confers resistance, in the context of R155K, is elucidated with drug susceptibility assays, crystal structures, and molecular dynamics (MD) simulations for three  ...  The R155K and R155K/V36M crystal structures differ in the α-2 helix and E2 strand near the active site, with alternative conformations at M36 and side chains of active site residues D168 and R123, revealing  ...  The loops connecting A1-B1 and E2-F2 strands, which can be thought of as "pseudo-flaps" in analogy to HIV-1 protease, were also closer to each other in the apo and danoprevir-bound proteases while the  ... 
doi:10.1101/452284 fatcat:2a5otlsvuzeivobh6ezevacevm

Retroviral Gag protein–RNA interactions: Implications for specific genomic RNA packaging and virion assembly

Erik D. Olson, Karin Musier-Forsyth
2018 Seminars in Cell and Developmental Biology  
Recent results have shed light on the role of MA and NC domain interactions with nucleic acids, and how they jointly function to ensure packaging of the retroviral gRNA.  ...  One of the critical functions of Gag is to specifically recognize, bind, and package the retroviral genomic RNA (gRNA) into assembling virions.  ...  Ioulia Rouzina and Mr. Shuohui Liu (Department of Chemistry and Biochemistry, The Ohio State University, Columbus, OH, USA) for helpful discussions and critical reading of the manuscript, and Dr.  ... 
doi:10.1016/j.semcdb.2018.03.015 pmid:29580971 pmcid:PMC6167211 fatcat:6yvu7cswgbesjh5znz2h7xabxa

HIV-1 Protease and Reverse Transcriptase Control the Architecture of Their Nucleocapsid Partner

Gilles Mirambeau, Sébastien Lyonnais, Dominique Coulaud, Laurence Hameau, Sophie Lafosse, Josette Jeusset, Isabelle Borde, Michèle Reboud-Ravaux, Tobias Restle, Robert J. Gorelick, Eric Le Cam, Martin Egli
2007 PLoS ONE  
The HIV-1 nucleocapsid is formed during protease (PR)-directed viral maturation, and is transformed into pre-integration complexes following reverse transcription in the cytoplasm of the infected cell.  ...  Here, we report a detailed transmission electron microscopy analysis of the impact of HIV-1 PR and reverse transcriptase (RT) on nucleocapsid plasticity, using in vitro reconstitutions.  ...  Hixson for their assistance in preparing mutant and wild-type NCp7, NCp9, NCp10 and NCp15 proteins and Bernie Greenwood for critical reading of the manuscript. Author Contributions  ... 
doi:10.1371/journal.pone.0000669 pmid:17712401 pmcid:PMC1940317 fatcat:x2g4vwyhabcw3mg46b2m7qfqba

Molecular Recognition in the Case of Flexible Targets

Anthony Ivetac, J. Andrew McCammon
2011 Current pharmaceutical design  
We review practical applications of the RCS and use a recent study of the HIV-1 reverse transcriptase to illustrate the various phases of the scheme.  ...  In this article, we discuss various methods and focus on the Relaxed Complex Scheme (RCS), which uses Molecular Dynamics (MD) simulations to model full protein flexibility and enhance virtual screening  ...  Acknowledgments This work has been supported in part by the National Science Foundation (NSF), the National Institutes of Health (NIH), the Howard Hughes Medical Institute (HHMI), the National Biomedical  ... 
doi:10.2174/138161211796355056 pmid:21619526 pmcid:PMC3271729 fatcat:6vh6x3kyjnd65hx7xnosovo34u

The role of quantum mechanics in structure-based drug design

Kaushik Raha, Martin B. Peters, Bing Wang, Ning Yu, Andrew M. Wollacott, Lance M. Westerhoff, Kenneth M. Merz
2007 Drug Discovery Today  
Objectively validating the improved applicability and performance of QM over classical-based models in DD will be the focus of research in the coming years along with research on the conformational sampling  ...  been shown that the expense of QM approaches is offset by improved accuracy in DD applications.  ...  Raha and Merz, again using DivCon, have also formulated a scheme to calculate the proton affinity of the catalytic aspartates of HIV-1 protease in the presence and absence of inhibitors bound to the proteases  ... 
doi:10.1016/j.drudis.2007.07.006 pmid:17826685 fatcat:43remmxxkng4vecjgmepuqwfni

Solution Conformation of Bovine Leukemia Virus Gag Suggests an Elongated Structure

Dominic F. Qualley, Sarah E. Cooper, James L. Ross, Erik D. Olson, William A. Cantara, Karin Musier-Forsyth
2019 Journal of Molecular Biology  
The models were used in molecular dynamic simulations to determine the relative mobility of the protein backbone.  ...  In this work, structural models of full-length BLV Gag and Gag lacking the MA domain were generated based on previous structural data of individual domains, homology modeling, and flexible fitting to SAXS  ...  Additional support comes from the National Institutes of Health project MINOS (R01 GM105404) and R01 GM065056 (to K. M.-F.).  ... 
doi:10.1016/j.jmb.2019.01.036 pmid:30731090 pmcid:PMC6424597 fatcat:nspytakobzfhbhiculp6swfl5y

Refinement of docked protein-ligand and protein-DNA structures using low frequency normal mode amplitude optimization

E. Lindahl
2005 Nucleic Acids Research  
Prediction of structural changes resulting from complex formation, both in ligands and receptors, is an important and unsolved problem in structural biology.  ...  In this work, we use all-atom normal modes calculated with the Elastic Network Model as a basis set to model structural flexibility during formation of macromolecular complexes and refine the nonbonded  ...  E.L. also wants to acknowledge É cole Normale Supérieure and Région Ile-de-France for kind support in the form of a Blaise Pascal fellowship. We thank Y.H.  ... 
doi:10.1093/nar/gki730 pmid:16087736 pmcid:PMC1183489 fatcat:7uf3qrucwngb5azlngf76hsr4m

X-ray Footprinting at Beamline X28C: A National Resource for Studying Macromolecular Structure and Dynamics

Rhijuta D'Mello, Sayan Gupta, Jen Bohon, Donald Abel, John Toomey, Michael Sullivan, Mark R. Chance
2009 Biophysical Journal  
The results of the simulations of fatty acyl derivatives will provide a first look at the manner in which ACP accommodates these binding groups.  ...  ACP is one of the most abundant proteins in Escherichia coli and possesses a large number of interacting enzymes.  ...  Molecular dynamic simulation of this receptor-correpressor complex system in the absence or presence of the ligand thyroid hormone has identified correlated conformational changes that may be important  ... 
doi:10.1016/j.bpj.2008.12.243 fatcat:hkz6hg3cjrdxlfk6qrmxuvhgti

A Novel Co-Crystal Structure Affords the Design of Gain-of-Function Lentiviral Integrase Mutants in the Presence of Modified PSIP1/LEDGF/p75

Stephen Hare, Ming-Chieh Shun, Saumya Shree Gupta, Eugene Valkov, Alan Engelman, Peter Cherepanov, Susan Ross
2009 PLoS Pathogens  
We now present a crystal structure containing the N-terminal and catalytic core domains ( NTD and CCD) of HIV-2 IN in complex with the IN binding domain (IBD) of LEDGF.  ...  Furthermore, the new structural details enabled us to engineer a mutant of HIV-1 IN that primarily functions only when presented with a complementary LEDGF mutant.  ...  Acknowledgments We are grateful to the staff of the ESRF beamlines ID23-1 and BM14 for assistance in data collection and to Professor S. Perkins and J.  ... 
doi:10.1371/journal.ppat.1000259 pmid:19132083 pmcid:PMC2606027 fatcat:bhgcjlmehnbrrojtxc3ofxniji

Structural and Thermodynamic Effects of Macrocyclization in HCV NS3/4A Inhibitor MK-5172

Djadé I. Soumana, Nese Kurt Yilmaz, Kristina L. Prachanronarong, Cihan Aydin, Akbar Ali, Celia A. Schiffer
2016 ACS Chemical Biology  
We have determined high-resolution crystal structures of linear and P1-P3 macrocyclic analogs of MK-5172 bound to WT and A156T protease and compared these structures, their molecular dynamics, and experimental  ...  alleviated in the linear and P1-P3 analogs.  ...  Smith from the Advanced Photon Source, LS-CAT beamline for data collection; W. Royer, A. Ozen  ... 
doi:10.1021/acschembio.5b00647 pmid:26682473 pmcid:PMC5099976 fatcat:olabhhibmzhnzgpbaensumk6am
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