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Novel Intersubunit Interaction Critical for HIV-1 Core Assembly Defines a Potentially Targetable Inhibitor Binding Pocket

Craveur, Pierrick and Gres, Anna T. and Kirby, Karen A. and Liu, Dandan and Hammond, John A. and Deng, Yisong and Forli, Stefano and Goodsell, David S. and Williamson, James R. and Sarafianos, Stefan G. and Olson, Arthur J. (2019) Novel Intersubunit Interaction Critical for HIV-1 Core Assembly Defines a Potentially Targetable Inhibitor Binding Pocket. mBio, 10 (2). Art. No. e02858-18. ISSN 2150-7511. PMCID PMC6414707. https://resolver.caltech.edu/CaltechAUTHORS:20190318-083009495

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Abstract

HIV-1 capsid protein (CA) plays critical roles in both early and late stages of the viral replication cycle. Mutagenesis and structural experiments have revealed that capsid core stability significantly affects uncoating and initiation of reverse transcription in host cells. This has led to efforts in developing antivirals targeting CA and its assembly, although none of the currently identified compounds are used in the clinic for treatment of HIV infection. A specific interaction that is primarily present in pentameric interfaces in the HIV-1 capsid core was identified and is reported to be important for CA assembly. This is shown by multidisciplinary characterization of CA site-directed mutants using biochemical analysis of virus-like particle formation, transmission electron microscopy of in vitro assembly, crystallographic studies, and molecular dynamic simulations. The data are consistent with a model where a hydrogen bond between CA residues E28 and K30′ from neighboring N-terminal domains (CA_(NTD)s) is important for CA pentamer interactions during core assembly. This pentamer-preferred interaction forms part of an N-terminal domain interface (NDI) pocket that is amenable to antiviral targeting.


Item Type:Article
Related URLs:
URLURL TypeDescription
https://doi.org/10.1128/mbio.02858-18DOIArticle
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6414707/PubMed CentralArticle
Additional Information:© 2019 Craveur et al. This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license. Received 21 December 2018; Accepted 7 January 2019; Published 12 March 2019. P.C. acknowledges Jean-Christophe Ducom for his support with high-performance computing resources. This is manuscript 29704 from TSRI. Use of the Advanced Photon Source, an Office of Science User Facility operated for the U.S. Department of Energy Office of Science by Argonne National Laboratory, was supported under contract DE-AC02-06CH11357. This work was supported in part by National Institutes of Health grants U54 GM103368 (to D.S.G., J.R.W., S.G.S., and A.J.O.) and R01 AI120860 (to S.G.S.). The funding agencies had no role in study design, data collection and interpretation, or the decision to submit the work for publication. Data availability: Structure factors and coordinates have been submitted to the RCSB Protein Data Bank (PDB) for the R18A, E28A, and R18A/E28A CA X-ray crystal structures (PDB IDs: 5W4O, 5W4P, and 5W4Q, respectively).
Funders:
Funding AgencyGrant Number
Department of Energy (DOE)DE-AC02-06CH11357
NIHU54 GM103368
NIHR01 AI120860
Issue or Number:2
PubMed Central ID:PMC6414707
Record Number:CaltechAUTHORS:20190318-083009495
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20190318-083009495
Official Citation:Novel Intersubunit Interaction Critical for HIV-1 Core Assembly Defines a Potentially Targetable Inhibitor Binding Pocket. Pierrick Craveur, Anna T. Gres, Karen A. Kirby, Dandan Liu, John A. Hammond, Yisong Deng, Stefano Forli, David S. Goodsell, James R. Williamson, Stefan G. Sarafianos, Arthur J. Olson. mBio Mar 2019, 10 (2) e02858-18; DOI: 10.1128/mBio.02858-18
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:93905
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:18 Mar 2019 16:14
Last Modified:03 Oct 2019 20:58

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