THE X-RAY CRYSTAL-STRUCTURE OF THROMBIN IN COMPLEX WITH N-ALPHA-2-NAPHTHYLSULFONYL-L-3-AMIDINO-PHENYLALANYL-4-METHYLPIPERIDIDE - THE BENEFICIAL EFFECT OF FILLING OUT AN EMPTY CAVITY

被引:17
作者
BERGNER, A
BAUER, M
BRANDSTETTER, H
STURZEBECHER, J
BODE, W
机构
[1] MAX PLANCK INST BIOCHEM, D-82152 MARTINSRIED, GERMANY
[2] KLINIKUM UNIV JENA, ZENTRUM VASKULARE BIOL & MED, D-99089 ERFURT, GERMANY
来源
JOURNAL OF ENZYME INHIBITION | 1995年 / 9卷 / 01期
关键词
THROMBIN; ANTITHROMBOTICS; INHIBITORS; X-RAY CRYSTAL STRUCTURE; INHIBITOR COMPLEX;
D O I
10.3109/14756369509040684
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The 2.5 Angstrom structure of bovine E-thrombin in complex with N alpha-2-naphthyl-sulfonyl-L-3-amidinophenylalanyl -4-methylpiperidide (L-NAPAMP) was solved and crystallographically refined to an R-value of 0.19. The L-NAPAMP moiety is completely and unambiguosly defined in the electron density. NAPAMP binds almost identical to the related 4-methyl deficient 3-amidino-phenylalanyl derivative TAPAP. The overall binding geometry appears dominated by the fixation of the 3-amidinophenyl ring in thrombin's S1-pocket and the hydrogen bonds to Gly 216, irrespective of the presence or absence of a substituent in the 4-position of the piperidine ring. The additional 4-methyl group gives rise to a 17-fold better binding. The more complete spatial occupancy of the hydrophobic S2-cavity therefore accounts for a decrease in free energy of binding of 15 kcal/mol, a value comparable with that anticipated for filling up a stable empty cavity of similar size by a methyl group.
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页码:101 / +
页数:1
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