Allosteric HIV‐1 integrase inhibitors promote aberrant protein multimerization by directly mediating inter‐subunit interactions: Structural and thermodynamic modeling studies
Open accessAbstract
Allosteric HIV‐1 integrase (IN) inhibitors (ALLINIs) bind at the dimer interface of the IN catalytic core domain (CCD), and potently inhibit HIV‐1 by promoting aberrant, higher‐order IN multimerization. Little is known about the structural organization of the inhibitor‐induced IN multimers and important questions regarding how ALLINIs promote aberrant IN multimerization remain to be answered. On the basis of physical chemistry principles and from our analysis of experimental information, we propose that inhibitor‐induced multimerization is mediated by ALLINIs directly promoting inter‐subunit interactions between the CCD dimer and a C‐terminal domain (CTD) of another IN dimer. Guided by this hypothesis, we have built atomic models of inter‐subunit interfaces in IN multimers by incorporating information from hydrogen‐deuterium exchange (HDX) measurements to drive protein‐protein docking. We have also developed a novel free energy simulation method to estimate the effects of ALLINI binding on the association of the CCD and CTD. Using this structural and thermodynamic modeling approach, we show that multimer inter‐subunit interface models can account for several experimental observations about ALLINI‐induced multimerization, including large differences in the potencies of various ALLINIs, the mechanisms of resistance mutations, and the crucial role of solvent exposed R‐groups in the high potency of certain ALLINIs. Our study predicts that CTD residues Tyr226, Trp235 and Lys266 are involved in the aberrant multimer interfaces. The key finding of the study is that it suggests the possibility of ALLINIs facilitating inter‐subunit interactions between an external CTD and the CCD‐CCD dimer interface.
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The common biochemical consequence of ALLINI binding is aberrant HIV-1 integrase hyper-multimerization.
“The common biochemical consequence of ALLINI binding is aberrant HIV-1 IN hyper-multimerization140,142,174–181.”
From Structure and function of retroviral integrase (2022) · cites this paper as [178]
Mass spectrometry footprinting, mutagenesis, and computational chemistry support this mode of integrase aggregation by ALLINIs.
“Solution measurements using mass spectrometry footprinting techniques, mutagenesis and computational chemistry strongly support this mode of IN aggregation by ALLINIs178,189.”
From Structure and function of retroviral integrase (2022) · cites this paper as [178]
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- Authors
- Deng, N., Hoyte, A., Mansour, Y. E., Mohamed, M. S., Fuchs, J. R., Engelman, A. N., Kvaratskhelia, M., & Levy, R.
- Affiliations
- Temple University (US)
- The Ohio State University (US)
- Helwan University (EG)
- Harvard University (US)
- Corresponding author
- Deng, Nanjie
- ORCID
- Venue
- Protein Science
- Publisher
- Wiley
- Published
- 2016-08-17
- Volume
- 25
- Issue
- 11
- Pages
- 1911-1917
- ISSN
- 0961-8368 (ISSN-L)
- 1469-896X
- PMC
- PMC5079246
- OpenAlex
- W2519497863
- Cited by
- 36
- References
- 29
- Citations by year
- 2026: 4 · 2025: 1 · 2024: 3 · 2023: 2 · 2022: 4 · 2021: 6 · 2020: 6 · 2019: 3 · 2018: 3 · 2017: 4
- FWCI
- 3.08
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Protein Science (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (P50GM103368 (to RML, ANE and MK), GM30580 (to RML), R01AI110310 (to MK and JRF))
- Topics
- Health Sciences › Medicine › Infectious Diseases › HIV/AIDS drug development and treatment
- Life Sciences › Immunology and Microbiology › Virology › HIV Research and Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Keywords
- HIV-1 integrase, integrase multimerization, intersubunit interactions, catalytic core domain, C-terminal domain, hydrogen-deuterium exchange, protein-protein docking, free energy simulation, drug resistance mutations, solvent-exposed residues
- MeSH terms
- Allosteric Regulation, Models, Chemical, Models, Molecular, Structure-Activity Relationship, HIV-1, HIV Integrase, HIV Integrase Inhibitors, Protein Multimerization
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