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Deng N , Hoyte A , Mansour YE , Mohamed MS , Fuchs JR , Engelman AN , Kvaratskhelia M , Levy R
Allosteric HIV-1 integrase inhibitors promote aberrant protein multimerization by directly mediating inter-subunit interactions: Structural and thermodynamic modeling studies
Protein Sci. 2016 Nov;25(11) :1911-1917
PMID: 27503276    PMCID: PMC5079246   
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Abstract
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.
Notes
1469-896x Deng, Nanjie Hoyte, Ashley Mansour, Yara E Mohamed, Mosaad S Fuchs, James R Engelman, Alan N Kvaratskhelia, Mamuka Levy, Ronald S10 RR027444/RR/NCRR NIH HHS/United States P50 GM103368/GM/NIGMS NIH HHS/United States R01 GM030580/GM/NIGMS NIH HHS/United States S10 OD020095/OD/NIH HHS/United States R01 AI110310/AI/NIAID NIH HHS/United States Journal Article United States Protein Sci. 2016 Nov;25(11):1911-1917. doi: 10.1002/pro.2997. Epub 2016 Aug 17.