Structure at 2.5-A resolution of chemically synthesized human immunodeficiency virus type 1 protease complexed with a hydroxyethylene-based inhibitor.

摘要: 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 R factor 0.138 at 2.5-A resolution. substrate-based inhibitor, H-Val-Ser-Gln-Asn-Leu psi [CH(OH)CH2]Val-Ile-Val-OH (U-85548e) contains hydroxyethylene isostere replacement the scissile bond that is believed mimic tetrahedral transition state proteolytic reaction. This potent Ki less than nM was developed as active-site titrant HIV-1 protease. binds in extended conformation involved beta-sheet interactions with floor flaps enzyme, which form substrate/inhibitor cavity. diastereomer S configuration chiral carbon atom insert, hydroxyl group within H-bonding distance two carboxyl groups enzyme dimer. subunits are related by pseudodyad, superposes them 178 degrees rotation. main difference beta turns flaps, have different conformations monomers. clear preferred orientation active site alternative conformation, if any, minor one (occupancy 30%). A new model enzymatic mechanism proposed reaction viewed one-step process during nucleophile (water molecule) electrophile (an acidic proton) attack concerted manner.