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| {{STRUCTURE_8hvp| PDB=8hvp | SCENE= }} | | {{STRUCTURE_8hvp| PDB=8hvp | SCENE= }} |
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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'''
| | ===STRUCTURE AT 2.5-ANGSTROMS RESOLUTION OF CHEMICALLY SYNTHESIZED HUMAN IMMUNODEFICIENCY VIRUS TYPE 1 PROTEASE COMPLEXED WITH A HYDROXYETHYLENE*-BASED INHIBITOR=== |
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| ==Overview==
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| 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.
| | The line below this paragraph, {{ABSTRACT_PUBMED_1993177}}, adds the Publication Abstract to the page |
| | (as it appears on PubMed at http://www.pubmed.gov), where 1993177 is the PubMed ID number. |
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| | {{ABSTRACT_PUBMED_1993177}} |
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| ==About this Structure== | | ==About this Structure== |
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| [[Category: Tomasselli, A G.]] | | [[Category: Tomasselli, A G.]] |
| [[Category: Wlodawer, A.]] | | [[Category: Wlodawer, A.]] |
| ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun May 4 22:49:34 2008'' | | |
| | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Fri Jul 11 12:53:29 2008'' |