2pxr: Difference between revisions

Revision as of 19:34, 21 February 2008

Crystal Structure of HIV-1 CA146 in the Presence of CAP-1

OverviewOverview

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 N) and inhibit capsid assembly during viral maturation. We have determined the structure of the complex between CA N and the antiviral assembly inhibitor N-(3-chloro-4-methylphenyl)-N'-{2-[({5-[(dimethylamino)-methyl]-2-furyl}-m ethyl)-sulfanyl]ethyl}-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.

About this StructureAbout this Structure

2PXR is a Single protein structure of sequence from Human immunodeficiency virus 1 with and as ligands. Full crystallographic information is available from OCA.

ReferenceReference

Structure of the antiviral assembly inhibitor CAP-1 complex with the HIV-1 CA protein., Kelly BN, Kyere S, Kinde I, Tang C, Howard BR, Robinson H, Sundquist WI, Summers MF, Hill CP, J Mol Biol. 2007 Oct 19;373(2):355-66. Epub 2007 Aug 15. PMID:17826792

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 ==Overview==
-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(N)) and inhibit capsid assembly during, viral maturation. We have determined the structure of the complex between, CA(N) and the antiviral assembly inhibitor, N-(3-chloro-4-methylphenyl)-N'-{2-[({5-[(dimethylamino)-methyl]-2-furyl}-m, ethyl)-sulfanyl]ethyl}-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.
+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 N) and inhibit capsid assembly during viral maturation. We have determined the structure of the complex between CA N and the antiviral assembly inhibitor N-(3-chloro-4-methylphenyl)-N'-{2-[({5-[(dimethylamino)-methyl]-2-furyl}-m ethyl)-sulfanyl]ethyl}-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.
 ==About this Structure==
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 ==Reference==
-Structure of the Antiviral Assembly Inhibitor CAP-1 Complex with the HIV-1 CA Protein., Kelly BN, Kyere S, Kinde I, Tang C, Howard BR, Robinson H, Sundquist WI, Summers MF, Hill CP, J Mol Biol. 2007 Aug 15;. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=17826792 17826792]
+Structure of the antiviral assembly inhibitor CAP-1 complex with the HIV-1 CA protein., Kelly BN, Kyere S, Kinde I, Tang C, Howard BR, Robinson H, Sundquist WI, Summers MF, Hill CP, J Mol Biol. 2007 Oct 19;373(2):355-66. Epub 2007 Aug 15. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=17826792 17826792]
 [[Category: Human immunodeficiency virus 1]]
 [[Category: Single protein]]
-[[Category: Kelly, B.N.]]
+[[Category: Kelly, B N.]]
 [[Category: CL]]
 [[Category: ZN]]
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 [[Category: viral protein]]
-''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Wed Jan 23 12:50:35 2008''
+''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 18:34:03 2008''