Origin of the stereospecificity in binding hydroxamates of α- and β-phenylalanine methylamide to thermolysin revealed by the X-ray crystallographic study
| Autor: | Seong Eon Ryu, Jung Dae Park, Joo Rang Woo, Yonghao Jin, Seung Jun Kim, Dong H. Kim |
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| Rok vydání: | 2003 |
| Předmět: |
Models
Molecular Denticity Stereochemistry Phenylalanine Clinical Biochemistry Thermolysin Pharmaceutical Science Crystallography X-Ray Hydroxamic Acids Biochemistry chemistry.chemical_compound Stereospecificity Drug Discovery Moiety Molecular Biology Binding Sites Hydroxamic acid biology Organic Chemistry Active site Stereoisomerism Methylamide Amides Crystallography chemistry biology.protein Molecular Medicine Enantiomer |
| Zdroj: | Bioorganic & Medicinal Chemistry. 11:2421-2426 |
| ISSN: | 0968-0896 |
| Popis: | Optically active N -formyl- N -hydroxy-α-phenylalanine methylamide ( 1 ) and N -formyl- N -hydroxy-β-phenylalanine methylamide ( 2 ) were evaluated as inhibitors for thermolysin (TLN) to find that while the d -form is more potent than its enantiomer in the case of the hydroxamate of α-Phe-NHMe, in the inhibition with hydroxamate of β-Phe-NHMe, the l -isomer ( K i =1.66±0.05 μM) is more effective than its enantiomer. In order to shed light on the stereochemical preference observed in the inhibitions, X-ray crystallographic analyses of the crystalline TLN· d - 1 and TLN· l - 2 complexes were performed to the resolution of 2.1 A. While l - 2 binds TLN like substrate does with its benzyl aromatic ring occupying the S 1 ′ pocket, the electron density in the S 1 ′ pocket in the complex of TLN· d - 1 is weak and could best be accounted for by the methylcarbamoyl moiety. For both inhibitors, the hydroxamate moiety coordinates the active site zinc ion in a bidentate fashion. |
| Databáze: | OpenAIRE |
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