PDBsum entry 2pxr

Viral protein

PDB id: 2pxr

Contents

Protein chain

145 a.a.

Metals

_ZN ×2

_CL

Waters ×179

PDB id:

2pxr

Name:

Viral protein

Title:

Crystal structure of HIV-1 ca146 in the presence of cap-1

Structure:

Gag-pol polyprotein (pr160gag-pol). Chain: c. Fragment: n-terminal domain

Source:

Human immunodeficiency virus 1. Organism_taxid: 11676. Strain: nl43

Resolution:

1.50Å R-factor: 0.166 R-free: 0.221

Authors:

B.N.Kelly

Key ref:

B.N.Kelly et al. (2007). Structure of the Antiviral Assembly Inhibitor CAP-1 Complex with the HIV-1 CA Protein. J Mol Biol, 373, 355-366. PubMed id: 17826792 DOI: 10.1016/j.jmb.2007.07.070

Date:

14-May-07 Release date: 25-Sep-07

Protein chain

Q79791  (Q79791_9HIV1) -  Gag polyprotein from Human immunodeficiency virus 1

Seq: 500 a.a.

Struc: 145 a.a.

Enzyme reactions

• Enzyme class: E.C.?

DOI no: 10.1016/j.jmb.2007.07.070

J Mol Biol 373:355-366 (2007)

PubMed id: 17826792

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

B.N.Kelly, S.Kyere, I.Kinde, C.Tang, B.R.Howard, H.Robinson, W.I.Sundquist, M.F.Summers, C.P.Hill.

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(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}-methyl)-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.

Selected figure(s)

Figure 4.
Figure 4. Representative CAP-1:CA^N structure calculated by restrained molecular dynamics using the hybrid X-ray/NMR approach. (a) Stereo view of the CAP-1 binding with observed NOEs (broken black lines) and potential hydrogen bonds (broken red lines) labeled. The side-chain of Phe32, which is displaced from the core upon CAP-1 binding, is also shown. (b) Electrostatic surface representation of the CAP-1 binding site showing the insertion of the CAP-1 aromatic ring into the pocket vacated by Phe32.

Figure 6.
Figure 6. (a) Model of the HIV-1 CA^N hexamer of the mature capsid lattice modeled on the MLV CA^N structure.^17 CAP-1 is shown in stick representation. (b) Orthogonal view. The approximate location of CA^C is indicated.

The above figures are reprinted from an Open Access publication published by Elsevier: J Mol Biol (2007, 373, 355-366) copyright 2007.

Figures were selected by an automated process.