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. 2016 Nov;25(11):1911-1917.
doi: 10.1002/pro.2997. Epub 2016 Aug 17.

Allosteric HIV-1 Integrase Inhibitors Promote Aberrant Protein Multimerization by Directly Mediating Inter-Subunit Interactions: Structural and Thermodynamic Modeling Studies

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Free PMC article

Allosteric HIV-1 Integrase Inhibitors Promote Aberrant Protein Multimerization by Directly Mediating Inter-Subunit Interactions: Structural and Thermodynamic Modeling Studies

Nanjie Deng et al. Protein Sci. .
Free PMC article

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.

Keywords: HIV-1 integrase; allosteric HIV-1 integrase inhibitor; protein-ligand binding; protein-protein docking.

Figures

Figure 1
Figure 1
(A) ALLINI KF116 (green stick) bound at the HIV‐1 IN CCD dimer interface. Subunit 1 and subunit 2 are shown in red and blue ribbons, respectively. (B) Pyridine‐based ALLINIs KF134 and KF116.
Figure 2
Figure 2
(A) Schematic diagram illustrating how ALLINI binding stabilizes the inter‐subunit interaction by expelling waters from the LEDGF/p75 binding pocket and increasing the effective protein‐protein interface. (B) Cartoon diagram showing a CTD of one IN dimer binding to the CCD‐CCD interface of another dimer in a chain reaction leading to higher order oligomerization, stabilized by the bound ALLINI at the CCD‐dimer interface.
Figure 3
Figure 3
Models of the inter‐subunit interface of IN multimers constructed using: (A) CTD and CCD‐ALLINI‐2; and (B) CTD and apo CCD. ALLINI‐2 is shown in green sticks in (A).
Figure 4
Figure 4
Comparisons of experimental antiviral activities of EC50 and calculated multimerization docking energies and the CCD binding affinities for several ALLINIs. The values of K d are converted from calculated values of binding free energy obtained from double decoupling calculations (Materials and Methods).

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