UNIQUE BINDING OF A NOVEL SYNTHETIC INHIBITOR, N-[3-[4-[4-(AMIDINOPHENOXY)CARBONYL]PHENYL]-2-METHYL-2-PROPENOY1]-N-ALLYLGLYCINE METHANESULFONATE, TO BOVINE TRYPSIN, REVEALED BY THE CRYSTAL-STRUCTURE OF THE COMPLEX

被引：12

作者：

ODAGAKI, Y ^{[1
]}

NAKAI, H ^{[1
]}

SENOKUCHI, K ^{[1
]}

KAWAMURA, M ^{[1
]}

HAMANAKA, N ^{[1
]}

NAKAMURA, M ^{[1
]}

TOMOO, K ^{[1
]}

ISHIDA, T ^{[1
]}

机构：

[1] OSAKA UNIV PHARMACEUT SCI,MATSUBARA,OSAKA 580,JAPAN

来源：

BIOCHEMISTRY | 1995年 / 34卷 / 39期

关键词：

D O I：

10.1021/bi00039a046

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：

Trypsin and N-[3-[4-[4-(amidinophenoxy)carbonyl]phenyl]-2-methyl-2-propenoyl]-N-allylglycine methanesulfonate (1), a newly designed and orally active synthetic trypsin inhibitor, were cocrystallized. The space group of the crystal is P2(1)2(1)2(1) with cell constants a = 63.74 Angstrom, b = 63.08 Angstrom, and c = 69.38 Angstrom, which is nearly identical to that of the orthorhombic crystal of guanidinobenzoyltrypsin. The structure was refined to a crystallographic residual R = 0.176. The refined model of the 1-trypsin complex provides the structural basis for the reaction mechanism of 1. On the basis of the present X-ray results, it is proposed that the potent inhibitory activity of 1 is mainly due to the formation of an acylated trypsin through an ''inverse substrate mechanism'' and its low rate of deacylation.

引用

页码：12849 / 12853

页数：5

共 14 条

[1] CRYSTAL-STRUCTURE OF BOVINE BETA-TRYPSIN AT 1.5-A RESOLUTION IN A CRYSTAL FORM WITH LOW-MOLECULAR PACKING DENSITY - ACTIVE-SITE GEOMETRY, ION-PAIRS AND SOLVENT STRUCTURE [J].