Origin of the stereospecificity in binding hydroxamates of α- and β-phenylalanine methylamide to thermolysin revealed by the X-ray crystallographic study
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- Origin of the stereospecificity in binding hydroxamates of α- and β-phenylalanine methylamide to thermolysin revealed by the X-ray crystallographic study
- Seung-Jun Kim; D H Kim; J D Park; Joo Rang Woo; Y H Jin; Seong Eon Ryu
- Bibliographic Citation
- Bioorganic & Medicinal Chemistry, vol. 11, no. 11, pp. 2421-2426
- Publication Year
- 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 (Ki=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 ?. While L-2 binds TLN like substrate does with its benzyl aromatic ring occupying the S1′ pocket, the electron density in the S1′ 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.
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