3bxr

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Revision as of 07:57, 26 March 2008

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spinqualitylabelsall models PDB ID 3bxr Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image
, resolution 1.600Å
Sites:	, , , and
Ligands:	, ,
Activity:	HIV-1 retropepsin, with EC number 3.4.23.16
Domains:	RVP
Resources:	FirstGlance, OCA, PDBsum, JenaLib, RCSB
Coordinates:	save as pdb, mmCIF, xml

Crystal Structures Of Highly Constrained Substrate And Hydrolysis Products Bound To HIV-1 Protease. Implications For Catalytic Mechanism

Overview

HIV-1 protease is a key target in treating HIV infection and AIDS, with 10 inhibitors used clinically. Here we used an unusual hexapeptide substrate, containing two macrocyclic tripeptides constrained to mimic a beta strand conformation, linked by a scissile peptide bond, to probe the structural mechanism of proteolysis. The substrate has been cocrystallized with catalytically active synthetic HIV-1 protease and an inactive isosteric (D25N) mutant, and three-dimensional structures were determined (1.60 A). The structure of the inactive HIVPR(D25N)/substrate complex shows an intact substrate molecule in a single orientation that perfectly mimics the binding of conventional peptide ligands of HIVPR. The structure of the active HIVPR/product complex shows two monocyclic hydrolysis products trapped in the active site, revealing two molecules of the N-terminal monocyclic product bound adjacent to one another, one molecule occupying the nonprime site, as expected, and the other monocycle binding in the prime site in the reverse orientation. The results suggest that both hydrolysis products are released from the active site upon cleavage and then rebind to the enzyme. These structures reveal that N-terminal binding of ligands is preferred, that the C-terminal site is more flexible, and that HIVPR can recognize substrate shape rather than just sequence alone. The product complex reveals three carboxylic acids in an almost planar orientation, indicating an unusual hexagonal homodromic complex between three carboxylic acids. The data presented herein regarding orientation of catalytic aspartates support the cleavage mechanism proposed by Northrop. The results imply strategies for design of inhibitors targeting the N-terminal side of the cleavage site or taking advantage of the flexibility in the protease domain that accommodates substrate/inhibitor segments C-terminal to the cleavage site.

About this Structure

3BXR is a Single protein structure of sequence from [1]. Full crystallographic information is available from OCA.

Reference

Crystal Structures of Highly Constrained Substrate and Hydrolysis Products Bound to HIV-1 Protease. Implications for the Catalytic Mechanism., Tyndall JD, Pattenden LK, Reid RC, Hu SH, Alewood D, Alewood PF, Walsh T, Fairlie DP, Martin JL, Biochemistry. 2008 Mar 25;47(12):3736-44. Epub 2008 Mar 1. PMID:18311928

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