HIV Interaction and Viral Evolution Center Research
The central theme of the HIVE Center is to further our structural and functional knowledge of HIV assembly, maturation, reverse transcription, and integration with the human host with the goal of determining the atomic resolution structures and the dynamic mechanisms of the macromolecular complexes involved in these processes. The ultimate aim is to relate this knowledge to the evolution of drug resistance and to the improvement of drug design methodologies in the treatment of HIV infected individuals.
This page includes publications from the HIVE Center (as compiled by NIH Reporter). Links are provided to the journal publication, the abstract at Pubmed, and in many cases, a free version of the full publication at Pubmed Central. Note that for some of the most recent articles, the Pubmed Central version may be embargoed by the journal for up to a year.
2017 Research Highlights
Physiological Mg2+ conditions significantly alter the inhibition of HIV-1 and HIV-2 reverse transcriptases by nucleoside and non-nucleoside inhibitors in vitro
The efficacy of RT inhibitors is dramatically affected by the level of magnesium, unscoring the need to test inhibitors using physiological conditions.
PubMed PMID: 27936595
An experimental check of backscattering interferometry
HIVE Center researchers validate BSI, a powerful method for rapid measuring of association constants.
RiboCAT: a new capillary electrophoresis data analysis tool for nucleic acid probing
A new software package streamlines the analysis of data that probes the structure of RNA.
PubMed PMID: 27821510
PMCID: PMC5238798 [Available on 2018-02-01]
Analysis of RNA structure using small-angle X-ray scattering
A review of best practices for using SAXS to determine the tertiary structure of RNA under physiological conditions.
PubMed PMID: 27777026
PMCID: PMC5253320 [Available on 2018-01-15]
Multidimensional SuFEx click chemistry: sequential sulfur(VI) fluoride exchange connection of diverse modules launched from an SOF4 hub.
A new family of transformations allow click chemistry connections between diverse chemical modules, including linkages between small molecules and protein sidechains.
PubMed PMID: 28165188
Cryo-EM structures and atomic model of the HIV-1 strand transfer complex intasome
Cryo-EM reveals tetrameric and higher-order assemblies of integrase within the HIV-1 intasome.
PubMed PMID: 28059769
2016 Research Highlights
Cryo-EM reveals a novel octameric integrase structure for betaretroviral intasome function
An unexpected octameric structure for a retroviral intasome is revealed using single-particle cryo-electron microscopy.
PubMed PMID: 26887496
PubMed Central PMCID: PMC4908968
Rapid experimental SAD phasing and hot-spot identification with halogenated fragments
Small molecules with halogens are shown to be an effective new tool for solving the phase problem in x-ray crystallography.
PubMed PMID: 26870381
PubMedCentral PMCID: PMC4704079
Fragment-based analysis of ligand dockings improves classification of actives
Results from virtual screening are analyzed to improve ranking of compounds for discovery of new inhibitors.
PubMedCentral PMCID: 5023760 (embargoed until Aug 2017)
Conformational states of HIV-1 reverse transcriptase for nucleotide incorporation vs pyrophosphorolysis--binding of foscarnet
A DNA aptamer is used to trap complexes of reverse transcriptase in a new structural state, providing insights for developing new inhibitors.
PubMed PMID: 27192549
PubMedCentral PMCID: PMC4992415 (embargoed until August 2017)
Allosteric HIV-1 integrase inhibitors promote aberrant protein multimerization by directly mediating inter-subunit interactions: structure and thermodynamic modeling studies
ALLINIs stabilize the interaction between integrase catalytic domains and C-terminal domains, causing aggregation that impares virus maturation.
PubMed PMID: 27503276
PMCID: PMC5079246 [Available on 2017-11-01]
The competitive interplay between allosteric HIV-1 integrase inhibitor BI/D and LEDGF/p75 during the early stage of HIV-1 replication adversely affects inhibitor potency
Binding of the cellular protein LEDGF/p17 blocks the multimerization of HIV-1 integrase by an ALLINI, reducing the inhibitor's antiviral activity.
PubMed PMID: 26910179
PubMedCentral PMCID: PMC4874862
Virological failure in patients with HIV-1 subtype C receiving antiretroviral therapy: an analysis of a prospective national cohort in Sweden
Analysis of clinical data reveals that patients with HIV-1C may have an increased risk of virological failure.
Pubmed PMID: 27036992
HIV-1 integrase binds the viral RNA genome and is essential during virion morphogenesis
A new role of integrase in formation of infectious HIV-1 particles is discovered.
PubMed PMID: 27565348
PubMedCenter PMCID: PMC5003418 (embargoed until August 2017)
Binding energy distribution analysis method: Hamiltonian replica exchange with torsional flattening for binding mode prediction and binding free energy estimation
A new method for broadening the reach of a computational search provides better estimates of an inhibitor's effectiveness.
PubMed PMID: 27070865
PubMedCentral PMCID: PMC4862910 (embargoed until May 2017)
Structure of HIV-1 reverse transcriptase bound to a novel 38-mer hairpin template-primer DNA aptamer
A DNA aptamer is used to determine the structure of reverse transcriptase without the need for crosslinking or a Fab.
PubMedCentral PMCID: 4815302 (embargoed until January 2017)
Factors influencing the efficacy of rilpivirine in HIV-1 subtype C in low- and middle-income countries
The development of resistance limits the use of rilpivirine as a first-line drug in HIV-1C-dominated epidemics.
PubMed PMID: 26518047
PubMedCentral PMCID: PMC4710214
A new class of allosteric HIV-1 integrase inhibitors identified by crystallographic fragment screening of the catalytic core domain
HIVE researchers have discovered a new lead for design of integrase inhibitors, which shows improved action against resitant mutants
PubMed PMID: 27645997
PMCID: PMC5095411 [Available on 2017-11-04]
Structural basis of HIV inhibition by translocation-defective RT inhibitor 4'-ethynyl-2-fluoro-2'-deoxyadenosine (EFdA)
HIVE researchers reveal the mechanism of action of the most potent nucleoside analog inhibitor of HIV reverse transcriptase.
PubMed PMID: 27489345
PubMed Central PMCID: PMC4995989 [Available on 2017-02-16]
Locally weighted histogram analysis and stochastic solution for large-scale multi-state free energy estimation
A fast and accurate new method for estimating binding free energies is reported.
PubMed PMID: 26801020
PubMedCentral PMCID: PMC4729400 (embargoed until January 2017)
Role of cysteines in stabilizing the randomized receptor binding domains within feline leukenia virus envelope proteins
Envelope protein is retargeted by addition of new cysteine amino acids.
PubMed Central PMCID: PMC4810629
Chemoselective synthesis of polysubstituted pyridines from hetroaryl fluorosulfates
A selective new method is reported for creating inhibitors with polysubstituted pyridines
PubMed PMID: 26990693
PubMedCentral PMCID: PMC4929982 (embargoed until April 2017)
2015 Research Highlights
The Future of HIV-1 Therapeutics: Resistance is Futile?
A review of current and future approaches to treatment of HIV-1.
Torbet, B. E., Goodsell, D. S. & Richman, D. D., eds.
Chapters from HIVE Center members:
HIV life cycle illustrations from the issue are available on in the Resources section of the HIVE Center site.
Alpha-carboxy nucleoside phosphonates as universal nucleoside triphosphate mimics
A new nucleotide scaffold was designed for use in inhibiting DNA polymerases and other targets.
Balzarini J, Das K, Bernatchez JA, Martinez SE, Ngure M, Keane S, Ford A, Maguire N, Mullins N, John J, Kim Y, Dehaen W, Vande Voorde J, Liekens S, Naesens L, Götte M, Maguire AR, Arnold E. Proc Natl Acad Sci U S A 112, 3475-80 (2015).
Distinguishing Binders from False Positives by Free Energy Calculations: Fragment Screening against the Flap Site of HIV Protease
The Binding Energy Distribution Analysis Method improves discrimination of binders and nonbinders in virtual screening results against HIV protease.
Deep Sequencing of Protease Inhibitor Resistant HIV Patient Isolates Reveals Patterns of Correlated Mutations in Gag and Protease
Deep sequencing of viruses from 93 patients has revealed mutations in Gag proteins contribute to recurrent treatment failure.
Distribution and redistribution of HIV-1 nucleocapsid in immature, mature, and integrase-inhibited virions: a role for integrase in maturation
An important role of integrase in packaging of the HIV-1 genome is revealed.
PubMed PMID: 26178982
PubMed Central PMCID: PMC4577894
Asynchronous replica exchange software for grid and heterogenous computing
Methods for performing molecular dynamics simulations on large clusters of computers are presented.
PubMed PMID: 27103749
PubMed Central PMCID: PMC4834714
Differential isotopic enrichment to facilitate characterization of asymmetric multimeric proteins using hydrogen/deuterium exchange mass spectrometry
By labeling the two subunits of reverse transcriptase with different isotopes of nitrogen, the subunits may be distinguished in hydrogen/deuterium exchange experiments.
X-ray structures of native HIV-1 capsid protein reveal conformational variability
A crystallographic structure of full-length HIV-1 capsid shows new variability in capsid assembly.
Pronounced inhibition shift from HIV reverse transcriptase to herpetic DNA polymerases by increasing the flexibility of alpha-carboxy nucleotide phosphates.
A new class of polymerase inhibitors is tuned to target different viruses.
PubMed PMID: 26450273
PubMed Central PMCID: PMC4893804
CellPACK: A Virtual Mesoscope to Model and Visualize Structural Systems Biology
A new method for creating 3D models of cellular systems is applied to the analysis of envelope glycoprotein distribution in HIV.
HCV glycoprotein structures: what to expect from the unexpected
Recent structural insights into the envelope glycoproteins of hepatitis C virus are reviewed.
Structural basis of clade-specific HIV-1 neutralization by humanized anti-V3 monoclonal antibody KD-247
Structure of an antibody that binds to HIV envelope glycoprotein reveals an unusual mode of interaction centered around the light chain of the antibody.
Fast hepatitis C virus RNA elimination and NS5A redistribution by NS5A inhibitors studied by multiplex assay approach
A new method is presented to assess the effectiveness of novel inhibitors of hepatitis C virus.
PubMed PMID: 25845863
PubMed Central PMCID: PMC4432190
Synthesis and properties of 2'-deoxy-2',4'-difluoroarabinose-modified nucleic acids
A modified nucleoside is used to build RNA strands that are more resistant to degradation, for use in gene silencing applications.
New structure sheds light on selective HIV-1 genomic RNA packaging
HIVE members review current work probing the structure and function of the HIV genome.
PubMed PMID: 26305251
PubMed Center PMCID: PMC4576207
CoVaMa: Co-variation Mapper for disequilibrium analysis of mutant loci in viral populations using next-generation sequence data
A new method has been developed to analyze linked variations in large sequence datasets from viral populations.
PubMed PMID: 26408523
PubMed Central PMCID: PMC4684750
Structural integrity of the ribonuclease H domain in HIV-1 reverse transcriptase
The role of several mutations in the folding of reverse transcriptase is revealed.
PubMed PMID: 26061827
PubMed Central PMCID: PMC4509971
Design, synthesis, biochemical, and antiviral evaluations of C6 benzyl and C6 biarylmethyl substituted 2-hydroxylisoquinoline-1,3-diones: dual inhibition agains HIV reverse transcriptase-associated RNase H and polymerase with antiviral activities
Inhibitors that block the RNase H site of reverse transcriptase have been discovered.
PubMed PMID: 25522204
PubMedCentral PMCID: PMC4306517
Role of the mammalian target of rapamycin pathway in lentiviral vector transduction of hematopoietic stem cells
Rapamycin improves lentiviral delivery of genes to hematopoietic stem cells.
PubMed Central PMCID: PMC4688901
Large-scale asynchronous and distributed multidimensional replical exchange molecular simulations and efficiency analysis
New methods are developed for rapid molecular dyamics simulations on large clusters of computers.
PubMed Central PMCID: PMC4512903
2014 Research Highlights
Mutations in HIV-1 reverse transcriptase affect the errors made in a single cycle of viral replication
Drug resistant forms of reverse transcriptase are shown to cause an unusual pattern of errors during viral replication.PubMed Central PMCID: PMC4054409
Antiviral drugs specific for coronaviruses in preclinical development
This review describes new inhibitors for SARS and MERS coronaviruses.
Evaluation of SSYA10-001 as a replication inhibitor of severe acute respiratory syndrome, mouse hepatitis, and Middle East respiratory syndrome coronaviruses
An inhibitor has been discovered that inhibits replication of three coronaviruses.
Undesired versus design enzymatic cleavage of linkers for liver targeting
A novel chemical method for selective release of drug molecules is presented.
PubMed PMID: 24461291
PubMedCentral PMCID: PMC4319531
Structures of HIV-1 RT-RNA/DNA Ternary Complexes with dATP and Nevirapine Reveal Conformational Flexibility of RNA/DNA: Insights into Requirements for RNase H Cleavage
Changes in the conformation of DNA and RNA may be important in the cleavage of RNA strands by RT.
Virtual Screening of Integrase Inhibitors by Large Scale Binding Free Energy Calculations: The SAMPL4 Challenge
The Binding Energy Distribution Analysis Method improves discrimination of binders and nonbinders in a docking challenge of inhibitors to integrase.
Advances in Targeting Nucleocapsid-Nucleic Acid Interactions in HIV-1 Therapy
The authors review approaches for fighting HIV with drugs that block the functions of nucleocapsid protein.
Structure of a dihydroxycoumarin active-site inhibitor in complex with the RNase H domain of HIV-1 reverse transcriptase and structure-activity analysis of inhibitor analogs
A new chemical scaffold has been validated for the design of HIV RNase H inhibitors.
PubMed PMID: 24840303
PubMedCentral PMCID: PMC4116331
SAMHD1 has differential impact on the efficacies of HIV nucleoside reverse transcriptase inhibitors
SAMHD1 is an enzyme that cleaves the nucleotides needed for HIV replication, but is shown to be less active against nucleotide reverse transcriptase inhibitors.
Structure of the core ectodomain of the hepatitis C virus envelope glycoprotein 2
The structure of the envelope glycoprotein of hepatitis C virus provides a new target for development of inhibitors and vaccines.
Molecular Mechanisms of Retroviral Integration Site Selection
HIVE researchers review the process of site selection in retroviral integration.
HDX-MS guided drug discovery: small molecules and biopharmaceuticals
HIVE Center researchers review methods for integrating HDX-MS into drug discovery programs.
PubMed PMID: 25179005
PubMed Central PMCID: PMC4253076
4'-Ethynyl-2-Fluoro-2'-Deoxyadenosine (Efda) Inhibits Hiv-1 Reverse Transcriptase with Multiple Mechanisms
EFdA blocks HIV RT by several mechanisms, making it an effective antiviral agent with a favorable resistance profile.
Michailidis, E., Huber, A. D., Ryan, E. M., Ong, Y. T., Leslie, M. D., Matzek, K. B., Singh, K., Marchand, B., Hagedorn, A. N., Kirby, K. A., Rohan, L. C., Kodama, E. N., Mitsuya, H., Parniak, M. A., and Sarafianos, S. G., J Biol Chem 289, 24533-24548 (2014).
Blind Prediction of HIV Integrase Binding from the SAMPL4 Challenge
Results from a docking challenge for inhibitors to integrase are reviewed.
Probing the molecular mechanism of action of the HIV-1 reverse transcriptase inhibitor 4'-ethynyl-2-fluoro-2'-deoxyadenosine (EFdA) using pre-steady-state kinetics
The inhibitor EFdA is added to a growing DNA chain by reverse transcriptase, then slows further extension of the DNA chain.
Ruthenium-catalyzed cycloaddition of 1-haloalkynes with nitrile oxides and organic azides; Synthesis of 4-halo isoxazoles and 5-halo triazoles
A new method is presented for inhibitor synthesis using click chemistry.
Advantages of crystallographic fragment screening: functional and mechanistic insights from a powerful platform for efficient drug discovery
The authors review a powerful method for using crystallography to discover new inhibitors.
Virtual Screening with AutoDock Vina and the Common Pharmacophore Engine of a Low Diversity Library of Fragments and Hits against the Three Allosteric Sites of HIV Integrase: Participation in the SAMPL4 Protein-Ligand Binding Challenge
HIVE members perform well in a docking challenge to predict the binding of inhibitors to integrase.
Phenyl substituted 4-hydroxypyridazine-3(2H)-ones and 5-hydroxypyridazin-4(3H)-ones: inhibitors of influenza A endonuclease
Inhibitors are tuned for action against influenza virus.
PubMed PMID: 25225968
PubMedCentral PMCID: PMC4191602
The P66 Immature Precursor of HIV-1 Reverse Transcriptase
NMR experiments reveal the mechanism of RT maturation.
A Critical Role of the C-Terminal Segment for Allosteric Inhibitor-Induced Aberrant Multimerization of HIV-1 Integrase
Mass spectrometry-based protein footprinting reveals that the C-terminal segment of integrase is important in multimerization by ALLINIs.
Drug Resistance in Non-B Subtype HIV-1: Impact of HIV-1 Reverse Transcriptase Inhibitors
HIVE members review how polymorphisms, transmission efficiency of drug-resistant strains, and differences in genetic barrier for drug resistance can differentially alter the response to reverse transcriptase-targeting therapies in various subtypes.
The Mechanism of H171T Resistance Reveals the Importance of N Inverted Question Mark -Protonated His171 for the Binding of Allosteric Inhibitor Bi-D to HIV-1 Integrase
The atomic basis of ALLINI resistance is revealed by crystallography.
Slaughter, A., Jurado, K. A., Deng, N., Feng, L., Kessl, J. J., Shkriabai, N., Larue, R. C., Fadel, H. J., Patel, P. A., Jena, N., Fuchs, J. R., Poeschla, E., Levy, R. M., Engelman, A., and Kvaratskhelia, M., Retrovirology 11, 100 (2014).
Crystallographic Fragment-Based Drug Discovery: Use of a Brominated Fragment Library Targeting HIV Protease
Brominated compounds are used to determine the position of small molecules bound to the HIV protease exosites.
Molecular dynamics study of HIV-1 RT-DNA-nevirapine complexes explains NNRTI inhibition and resistance by connection mutations
Computational analysis gives new insight into the dynamic coupling of subdomains in RT, and their implications for drug resistance.
PubMed PMID: 24174331
PubMedCentral PMCID: PMC4502926
Rapamycin relieves lentiviral vector transduction resistance in human and mouse hematopoietic stem cells
Potential treatments for HIV infection using genetically-modified hematopoietic stem cells may be enhanced with rapamycin.
PubMed PMID: 24914132
PubMed Central PMCID: PMC4126331
2013 Research Highlights
Detecting allosteric sites of HIV-1 reverse transcriptase by X-ray crystallographic fragment screening
New sites for the design of inhibitors are discovered throughout the structure of HIV RT.
PubMed PMID: 23342998
PubMedCentral PMCID: PMC3906421
Rapid deep sequencing of patient-derived HIV with ion semiconductor technology
Ion Torrent devices are used for deep sequencing of drug resistant HIV samples, yielding high levels of sequencing coverage in HIV Gag and protease, and allowing the detection of mutations at low frequencies.
HIV-1 reverse transcriptase and antiviral drug resistance
A discussion of the current state of understanding of RT structure and function, and mechanisms of drug resistance.
PubMed PMID: 23602471
PubMed PMID: 23602470
PubMedCentral PMCID: PMC4097817
Allosteric Inhibition of HIV-1 Integrase Activity
A review of progress with the development of allosteric integrase inhibitors (ALLINIs) that compete with LEDGF/p75 for binding to integrase, disrupting viral maturation and inhibiting integrase function.
The A128T Resistance Mutation Reveals Aberrant Protein Multimerization as the Primary Mechanism of Action of Allosteric HIV-1 Integrase Inhibitors
A new resistance mutation in HIV integrase reveals an unexpected mechanism for action for integrase inhibitors.
Evaluation of Combinations of 4'-Ethynyl-2-Fluoro-2'-Deoxyadenosine with Clinically Used Antiretroviral Drugs
The potent antiviral activity of EfdA is found to be synergistic with rilpivirine.
Hachiya, A., Reeve, A. B., Marchand, B., Michailidis, E., Ong, Y. T., Kirby, K. A., Leslie, M. D., Oka, S., Kodama, E. N., Rohan, L. C., Mitsuya, H., Parniak, M. A., and Sarafianos, S. G., Antimicrob Agents Chemother (2013).
Multimodal mechanism of action of allosteric HIV-1 integrase inhibitors
A review of the action of ALLINIs and their use in study of integrase function in the HIV life cycle.
PubMed PMID: 24274067
Allosteric Integrase Inhibitor Potency is Determined Through the Inhibition of HIV-1 Particle Maturation
Allosteric integrase inhibitors, originally developed to block viral integration, are also surprisingly found to be potent inhibitors of viral maturation.
Effects of Substitutions at the 4' and 2 Positions on the Bioactivity of 4'-Ethynyl-2-Fluoro-2'-Deoxyadenosine
The structural basis of the potent antiviral activity of EFdA is revealed.
Kirby, K. A., Michailidis, E., Fetterly, T. L., Steinbach, M. A., Singh, K., Marchand, B., Leslie, M. D., Hagedorn, A. N., Kodama, E. N., Marquez, V. E., Hughes, S. H., Mitsuya, H., Parniak, M. A., and Sarafianos, S. G., Antimicrob Agents Chemother 57, 6254-6264 (2013).
Snapshot of the equlibrium dynamics of a drug bound to HIV-1 reverse transcriptase
Spectroscopy, crystallography and computer simulation are used to probe the dynamics of HIV RT when interacting with rilpivirine.
PubMed PMID: 23422558
PubMedCentral PMCID: PMC3607437
Hypersusceptibility Mechanism of Tenofovir-Resistant HIV to EFdA
A significant decrease in excision efficiency makes EFdA effective against drug resistant HIV RT.
Michailidis, E., Ryan, E. M., Hachiya, A., Kirby, K. A., Marchand, B., Leslie, M. D., Huber, A. D., Ong, Y. T., Jackson, J. C., Singh, K., Kodama, E. N., Mitsuya, H., Parniak, M. A., and Sarafianos, S. G., Retrovirology 10, 65 (2013).
AutoDrug: fully automated macromolecular crystallography workflows for fragment-based drug screening
HIVE researchers have developed software that automates the entire process of crystallographic fragment screening for the discovery of inhibitors.
PubMed PMID: 23633588
PubMedCentral PMCID: PMC3640469
Viral precursor polypeptides: key of regulation from replication to maturation
Four recent structures of viral polyprotein precursors are reviewed.
PubMed PMID: 23602469
PubMedCentral PMCID: PMC3660988
Fragment screening and HIV therapeutics
Fragment screening is reviewed, providing opportunities for discovery of novel anti-HIV drugs.
PubMed PMID: 21972022
PubMedCentral PMCID: PMC3565459
Identification of HIV-1 Inhibitors Targeting the Nucleocapsid Protein
A high-throughput assay is used to discover drugs that block the action of HIV nucleocapsid
HIV-1 Reverse Transcriptase Complex with DNA and Nevirapine Reveals Non-nucleoside Inhibition Mechanism
The crystal structures of reverse transcriptase with DNA and two types of inhibitors have been solved. The RT-DNA complex in the crystal could bind either the non-nucleoside inhibitor nevirapine or the nucleoside inhibitor AST-triphosphate, but not both. The structures reveal the complementary roles these different classes of inhibitor play in widely-used anti-AIDS therapies.
Retroviral Intasome Assembly and Inhibition of DNA Strand Transfer
The structure was solved of full-length retroviral integrase from prototype foamy virus in complex with its cognate DNA. The structure shows the organization of retroviral intasome , with an integrase tetramer tightly associated with a pair of viral DNA ends. The structure reveals the extensive protein-DNA and protein-protein interactions involved in retroviral integration, and provides a model for the HIV-1 intasome.
A comparison of the ability of rilpivirine (TMC278) and selected analogues to inhibit clinically relevant HIV-1 reverse transcriptase mutants.
A combination of structure activity relationships and X-ray crystallography was used to examine non-nucleoside reverse transcriptase inhibitors that are structurally related to rilpivirine to determine their ability to inhibit wildtype reverse transcriptase and several clinically relevant mutants.
3D Molecular Models of Whole HIV-1 Virions Generated with CellPACK
Methods for creating 3D models of mature HIV are presented.PubMedCentral PMCID: PMC4569901
Snapshot of the equilibrium dynamics of a drug bound to HIV-1 reverse transcriptase.
Femtosecond experiments and theory expose the molecular level dynamics of rilpivirine bound to HIV-1 RT.
Fragment-Based Screen Against HIV Protease
Two new inhibitor binding sites were discovered on wild-type HIV protease using fragment-based screening techniques. Protease was cocrystallized or soaked with chemical fragments using five different crystal forms, and 378 data sets were collected. Fragment binding induces a new conformation and crystal form in protease with the active site inhibitor TL-3. This study is the first fragment-based crystallographic screen against HIV protease, revealing two new exosites that stabilize inhibitor binding at the active site.
The alphavirus replication machinery consists of four nonstructural proteins produced as a single polyprotein. The structure has been solved of P23 in a precleavage form. The P2/3 cleavage site is located at the base of a narrow cleft and is not readily accessible, and the nsP2 protease active site is over 40 Angstroms away, supporting a regulated, trans cleavage mechanism.
Theory of binless multi-state free energy estimation with applications to protein-ligand binding.
The paper describes a simplified technique for computing free energies and expectations from multiple ensembles.
Small Molecule Regulation of Protein Conformation by Binding in the Flap of HIV Protease
Crystallographic structures of two small indoles reveal a binding site that favors a closed conformation of the HIV protease flaps.
T. Tiefenbrunn, S. Forli, M. M. Baksh, M. W. Chang, M. Happer, Y.-C. Lin, A. L. Perryman, J.-K. Rhee, B. E. Torbett, A. J. Olson, J. H. Elder, M. G. Finn & C. D. Stout. ACS Chem Biol 8, 1223-1231 (2013)