Inhibition of human immunodeficiency virus-1 protease by a C2-symmetric phosphinate. Synthesis and crystallographic analysis
| Autor: | S S, Abdel-Meguid, B, Zhao, K H, Murthy, E, Winborne, J K, Choi, R L, DesJarlais, M D, Minnich, J S, Culp, C, Debouck, T A, Tomaszek |
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| Rok vydání: | 1993 |
| Předmět: |
Models
Molecular Stereochemistry medicine.medical_treatment Molecular Sequence Data Molecular Conformation Phosphinate Biochemistry Catalysis chemistry.chemical_compound Organophosphorus Compounds Sugar Alcohols HIV Protease X-Ray Diffraction Penicillopepsin medicine Moiety Amino Acid Sequence Protease Binding Sites biology Hydrogen bond Active site Valine HIV Protease Inhibitors Phosphonate Phosphinic Acids Recombinant Proteins Crystallography chemistry Enzyme inhibitor biology.protein HIV-1 Crystallization Protein Binding |
| Zdroj: | Biochemistry. 32(31) |
| ISSN: | 0006-2960 |
| Popis: | 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) |
| Databáze: | OpenAIRE |
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