8hvp
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STRUCTURE AT 2.5-ANGSTROMS RESOLUTION OF CHEMICALLY SYNTHESIZED HUMAN IMMUNODEFICIENCY VIRUS TYPE 1 PROTEASE COMPLEXED WITH A HYDROXYETHYLENE*-BASED INHIBITOR
OverviewOverview
The crystal structure of a complex between chemically synthesized human, immunodeficiency virus type 1 (HIV-1) protease and an octapeptide, inhibitor has been refined to an R factor of 0.138 at 2.5-A resolution., The substrate-based inhibitor, H-Val-Ser-Gln-Asn-Leu psi, [CH(OH)CH2]Val-Ile-Val-OH (U-85548e) contains a hydroxyethylene isostere, replacement at the scissile bond that is believed to mimic the tetrahedral, transition state of the proteolytic reaction. This potent inhibitor has Ki, less than 1 nM and was developed as an active-site titrant of the HIV-1, protease. The inhibitor binds in an extended conformation and is involved, in beta-sheet interactions with the active-site floor and flaps of the, enzyme, which form the substrate/inhibitor cavity. The inhibitor, diastereomer has the S configuration at the chiral carbon atom of the, hydroxyethylene insert, and the hydroxyl group is within H-bonding, distance of the two active-site carboxyl groups in the enzyme dimer. The, two subunits of the enzyme are related by a pseudodyad, which superposes, them at a 178 degrees rotation. The main difference between the subunits, is in the beta turns of the flaps, which have different conformations in, the two monomers. The inhibitor has a clear preferred orientation in the, active site and the alternative conformation, if any, is a minor one, (occupancy of less than 30%). A new model of the enzymatic mechanism is, proposed in which the proteolytic reaction is viewed as a one-step process, during which the nucleophile (water molecule) and electrophile (an acidic, proton) attack the scissile bond in a concerted manner.
About this StructureAbout this Structure
8HVP is a Single protein structure of sequence from Human immunodeficiency virus 1. Full crystallographic information is available from OCA.
ReferenceReference
Structure at 2.5-A resolution of chemically synthesized human immunodeficiency virus type 1 protease complexed with a hydroxyethylene-based inhibitor., Jaskolski M, Tomasselli AG, Sawyer TK, Staples DG, Heinrikson RL, Schneider J, Kent SB, Wlodawer A, Biochemistry. 1991 Feb 12;30(6):1600-9. PMID:1993177
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