8HVP

STRUCTURE AT 2.5-ANGSTROMS RESOLUTION OF CHEMICALLY SYNTHESIZED HUMAN IMMUNODEFICIENCY VIRUS TYPE 1 PROTEASE COMPLEXED WITH A HYDROXYETHYLENE*-BASED INHIBITOR

Summary for 8HVP

• Entry DOI: 10.2210/pdb8hvp/pdb
• Related PRD ID: PRD_000362
• Descriptor: HIV-1 PROTEASE, INHIBITOR VAL-SER-GLN-ASN-LEU-PSI(CH(OH)-CH2)-VAL-ILE-VAL (U-85548E) (3 entities in total)
• Functional Keywords: acid proteinase, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Human immunodeficiency virus 1
• Cellular location: Gag-Pol polyprotein: Host cell membrane; Lipid-anchor. Matrix protein p17: Virion membrane; Lipid- anchor . Capsid protein p24: Virion . Nucleocapsid protein p7: Virion . Reverse transcriptase/ribonuclease H: Virion . Integrase: Virion : P03369
• Total number of polymer chains: 3
• Total formula weight: 22401.33

Authors

Jaskolski, M.,Miller, M.,Tomasselli, A.G.,Sawyer, T.K.,Staples, D.G.,Heinrikson, R.L.,Schneider, J.,Kent, S.B.H.,Wlodawer, A. (deposition date: 1990-10-26, release date: 1993-10-31, Last modification date: 2023-11-15)

Primary citation

Jaskolski, M.,Tomasselli, A.G.,Sawyer, T.K.,Staples, D.G.,Heinrikson, R.L.,Schneider, J.,Kent, S.B.,Wlodawer, A.
Structure at 2.5-A resolution of chemically synthesized human immunodeficiency virus type 1 protease complexed with a hydroxyethylene-based inhibitor.
Biochemistry, 30:1600-1609, 1991

PubMed Abstract: 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.

PubMed: 1993177
DOI: 10.1021/bi00220a023

Experimental method

X-RAY DIFFRACTION (2.5 Å)