1HOS
INHIBITION OF HUMAN IMMUNODEFICIENCY VIRUS-1 PROTEASE BY A C2-SYMMETRIC PHOSPHINATE SYNTHESIS AND CRYSTALLOGRAPHIC ANALYSIS
Summary for 1HOS
Entry DOI | 10.2210/pdb1hos/pdb |
Descriptor | HIV-1 PROTEASE, (2-PHENYL-1-CARBOBENZYL-OXYVALYL-AMINO)-ETHYL-PHOSPHINIC ACID (3 entities in total) |
Functional Keywords | hydrolase(acid proteinase) |
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 : P03366 |
Total number of polymer chains | 2 |
Total formula weight | 22378.36 |
Authors | Abdel-Meguid, S.,Zhao, B. (deposition date: 1993-04-06, release date: 1993-10-31, Last modification date: 2024-02-07) |
Primary citation | Abdel-Meguid, S.S.,Zhao, B.,Murthy, K.H.,Winborne, E.,Choi, J.K.,DesJarlais, R.L.,Minnich, M.D.,Culp, J.S.,Debouck, C.,Tomaszek Jr., T.A.,Meek, T.D.,Dreyer, G.B. Inhibition of human immunodeficiency virus-1 protease by a C2-symmetric phosphinate. Synthesis and crystallographic analysis. Biochemistry, 32:7972-7980, 1993 Cited by PubMed Abstract: The human immunodeficiency virus type 1 (HIV-1) protease is a potential target of acquired immune deficiency syndrome (AIDS) therapy. A highly potent, perfectly symmetrical phosphinate inhibitor of this enzyme, SB204144, has been synthesized. It is a competitive inhibitor of HIV-1 protease, with an apparent inhibition constant of 2.8 nM at pH 6.0. The three-dimensional structure of SB204144 bound to the enzyme has been determined at 2.3-A resolution by X-ray diffraction techniques and refined to a crystallographic discrepancy factor, R (= sigma parallel F(o) magnitude to - Fc parallel/sigma magnitude of F(o)), of 0.178. The inhibitor is held in the enzyme active site by a set of hydrophobic and hydrophilic interactions, including an interaction between Arg8 and the center of the terminal benzene rings of the inhibitor. The phosphinate establishes a novel interaction with the two catalytic aspartates; each oxygen of the central phosphinic acid moiety interacts with a single oxygen of one aspartic acid, establishing a very short (2.2-2.4 A) oxygen-oxygen contact. As with the structures of penicillopepsin bound to phosphinate and phosphonate inhibitors [Fraser, M. E., Strynadka, N. C., Bartlett, P. A., Hanson, J. E., & James, M. N. (1992) Biochemistry 31, 5201-14], we interpret this short distance and the stereochemical environment of each pair of oxygens in terms of a hydrogen bond that has a symmetric single-well potential energy curve with the proton located midway between the two atoms.(ABSTRACT TRUNCATED AT 250 WORDS) PubMed: 8347601DOI: 10.1021/bi00082a019 PDB entries with the same primary citation |
Experimental method | X-RAY DIFFRACTION (2.3 Å) |
Structure validation
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