1b6l

File:1b6l.jpg

spinqualitylabelsall models 1b6l, resolution 1.75Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

HIV-1 PROTEASE COMPLEXED WITH MACROCYCLIC PEPTIDOMIMETIC INHIBITOR 4

OverviewOverview

High-resolution crystal structures are described for seven macrocycles, complexed with HIV-1 protease (HIVPR). The macrocycles possess two amides, and an aromatic group within 15-17 membered rings designed to replace N-, or C-terminal tripeptides from peptidic inhibitors of HIVPR. Appended to, each macrocycle is a transition state isostere and either an acyclic, peptide, nonpeptide, or another macrocycle. These cyclic analogues are, potent inhibitors of HIVPR, and the crystal structures show them to be, structural mimics of acyclic peptides, binding in the active site of HIVPR, via the same interactions. Each macrocycle is restrained to adopt a, beta-strand conformation which is preorganized for protease binding. An, unusual feature of the binding of C-terminal macrocyclic inhibitors is the, interaction between a positively charged secondary amine and a catalytic, aspartate of HIVPR. A bicyclic inhibitor binds similarly through its, secondary amine that lies between its component N-terminal and C-terminal, macrocycles. In contrast, the corresponding tertiary amine of the, N-terminal macrocycles does not interact with the catalytic aspartates., The amine-aspartate interaction induces a 1.5 A N-terminal translation of, the inhibitors in the active site and is accompanied by weakened, interactions with a water molecule that bridges the ligand to the enzyme, as well as static disorder in enzyme flap residues. This flexibility may, facilitate peptide cleavage and product dissociation during catalysis., Proteases [Aba67,95]HIVPR and [Lys7,Ile33,Aba67,95]HIVPR used in this work, were shown to have very similar crystal structures.

About this StructureAbout this Structure

1B6L is a Single protein structure of sequence from Human immunodeficiency virus type 1 (isolate arv2/sf2) with and as ligands. Active as HIV-1 retropepsin, with EC number 3.4.23.16 Full crystallographic information is available from OCA.

ReferenceReference

Molecular recognition of macrocyclic peptidomimetic inhibitors by HIV-1 protease., Martin JL, Begun J, Schindeler A, Wickramasinghe WA, Alewood D, Alewood PF, Bergman DA, Brinkworth RI, Abbenante G, March DR, Reid RC, Fairlie DP, Biochemistry. 1999 Jun 22;38(25):7978-88. PMID:10387041

Page seeded by OCA on Fri Feb 15 15:31:01 2008