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Title: Structure of the Antiviral Assembly Inhibitor CAP-1 Complex with the HIV-1 CA Protein

Abstract

The CA domain of the human immunodeficiency virus type 1 (HIV-1) Gag polyprotein plays critical roles in both the early and late phases of viral replication and is therefore an attractive antiviral target. Compounds with antiviral activity were recently identified that bind to the N-terminal domain of CA (CA{sup N}) and inhibit capsid assembly during viral maturation. We have determined the structure of the complex between CA{sup N} and the antiviral assembly inhibitor N-(3-chloro-4-methylphenyl)-N'-{l_brace}2-[({l_brace}5-[(dimethylamino)-methyl]-2-furyl{r_brace}-methyl)-sulfanyl]ethyl{r_brace}-urea (CAP-1) using a combination of NMR spectroscopy and X-ray crystallography. The protein undergoes a remarkable conformational change upon CAP-1 binding, in which Phe32 is displaced from its buried position in the protein core to open a deep hydrophobic cavity that serves as the ligand binding site. The aromatic ring of CAP-1 inserts into the cavity, with the urea NH groups forming hydrogen bonds with the backbone oxygen of Val59 and the dimethylamonium group interacting with the side-chains of Glu28 and Glu29. Elements that could be exploited to improve binding affinity are apparent in the structure. The displacement of Phe32 by CAP-1 appears to be facilitated by a strained main-chain conformation, which suggests a potential role for a Phe32 conformational switch during normal capsid assembly.

Authors:
; ; ; ; ; ; ; ;
Publication Date:
Research Org.:
Brookhaven National Laboratory (BNL) National Synchrotron Light Source
Sponsoring Org.:
Doe - Office Of Science
OSTI Identifier:
930045
Report Number(s):
BNL-80670-2008-JA
Journal ID: ISSN 0022-2836; JMOBAK; TRN: US200822%%1277
DOE Contract Number:  
DE-AC02-98CH10886
Resource Type:
Journal Article
Resource Relation:
Journal Name: Journal of Molecular Biology; Journal Volume: 373; Journal Issue: 2
Country of Publication:
United States
Language:
English
Subject:
08 HYDROGEN; AFFINITY; AIDS; AROMATICS; CONFORMATIONAL CHANGES; CRYSTALLOGRAPHY; ELEMENTS; HUMAN POPULATIONS; HYDROGEN; LIGANDS; MATURATION; NMR IMAGING; NUCLEAR MAGNETIC RESONANCE; OXYGEN; PROTEINS; SPECTROSCOPY; UREA; X-RAY DIFFRACTION; national synchrotron light source

Citation Formats

Kelly,B., Kyere, S., Kinde, I., Tang, C., Howard, B., Robinson, H., Sundquist, W., Summers, M., and Hill, C.. Structure of the Antiviral Assembly Inhibitor CAP-1 Complex with the HIV-1 CA Protein. United States: N. p., 2007. Web. doi:10.1016/j.jmb.2007.07.070.
Kelly,B., Kyere, S., Kinde, I., Tang, C., Howard, B., Robinson, H., Sundquist, W., Summers, M., & Hill, C.. Structure of the Antiviral Assembly Inhibitor CAP-1 Complex with the HIV-1 CA Protein. United States. doi:10.1016/j.jmb.2007.07.070.
Kelly,B., Kyere, S., Kinde, I., Tang, C., Howard, B., Robinson, H., Sundquist, W., Summers, M., and Hill, C.. Mon . "Structure of the Antiviral Assembly Inhibitor CAP-1 Complex with the HIV-1 CA Protein". United States. doi:10.1016/j.jmb.2007.07.070.
@article{osti_930045,
title = {Structure of the Antiviral Assembly Inhibitor CAP-1 Complex with the HIV-1 CA Protein},
author = {Kelly,B. and Kyere, S. and Kinde, I. and Tang, C. and Howard, B. and Robinson, H. and Sundquist, W. and Summers, M. and Hill, C.},
abstractNote = {The CA domain of the human immunodeficiency virus type 1 (HIV-1) Gag polyprotein plays critical roles in both the early and late phases of viral replication and is therefore an attractive antiviral target. Compounds with antiviral activity were recently identified that bind to the N-terminal domain of CA (CA{sup N}) and inhibit capsid assembly during viral maturation. We have determined the structure of the complex between CA{sup N} and the antiviral assembly inhibitor N-(3-chloro-4-methylphenyl)-N'-{l_brace}2-[({l_brace}5-[(dimethylamino)-methyl]-2-furyl{r_brace}-methyl)-sulfanyl]ethyl{r_brace}-urea (CAP-1) using a combination of NMR spectroscopy and X-ray crystallography. The protein undergoes a remarkable conformational change upon CAP-1 binding, in which Phe32 is displaced from its buried position in the protein core to open a deep hydrophobic cavity that serves as the ligand binding site. The aromatic ring of CAP-1 inserts into the cavity, with the urea NH groups forming hydrogen bonds with the backbone oxygen of Val59 and the dimethylamonium group interacting with the side-chains of Glu28 and Glu29. Elements that could be exploited to improve binding affinity are apparent in the structure. The displacement of Phe32 by CAP-1 appears to be facilitated by a strained main-chain conformation, which suggests a potential role for a Phe32 conformational switch during normal capsid assembly.},
doi = {10.1016/j.jmb.2007.07.070},
journal = {Journal of Molecular Biology},
number = 2,
volume = 373,
place = {United States},
year = {Mon Jan 01 00:00:00 EST 2007},
month = {Mon Jan 01 00:00:00 EST 2007}
}