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1bb0

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{{STRUCTURE_1bb0| PDB=1bb0 | SCENE= }}
{{STRUCTURE_1bb0| PDB=1bb0 | SCENE= }}
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'''THROMBIN INHIBITORS WITH RIGID TRIPEPTIDYL ALDEHYDES'''
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===THROMBIN INHIBITORS WITH RIGID TRIPEPTIDYL ALDEHYDES===
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==Overview==
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The crystal structures of three highly potent and selective low-molecular weight rigid peptidyl aldehyde inhibitors complexed with thrombin have been determined and refined to R values 0.152-0. 170 at 1.8-2.1 A resolution. Since the selectivity of two of the inhibitors was &gt;1600 with respect to trypsin, the structures of trypsin-inhibited complexes of these inhibitors were also determined (R = 0.142-0.157 at 1.9-2.1 A resolution). The selectivity appears to reside in the inability of a benzenesulfonamide group to bind at the equivalent of the D-enantiomorphic S3 site of thrombin, which may be related to the lack of a 60-insertion loop in trypsin. All the inhibitors have a novel lactam moiety at the P3 position, while the two with greatest trypsin selectivity have a guanidinopiperidyl group at the P1 position that binds in the S1 specificity site. Differences in the binding constants of these inhibitors are correlated with their interactions with thrombin and trypsin. The kinetics of inhibition vary from slow to fast with thrombin and are fast in all cases with trypsin. The kinetics are examined in terms of the slow formation of a stable transition-state complex in a two-step mechanism. The structures of both thrombin and trypsin complexes show similar well-defined transition states in the S1 site and at the electrophilic carbon atom and Ser195OG. The trypsin structures, however, suggest that the first step in a two-step kinetic mechanism may involve formation of a weak transition-state complex, rather than binding dominated by the P2-P4 positions.
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(as it appears on PubMed at http://www.pubmed.gov), where 9724521 is the PubMed ID number.
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{{ABSTRACT_PUBMED_9724521}}
==About this Structure==
==About this Structure==
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[[Category: Zhang, E.]]
[[Category: Zhang, E.]]
[[Category: Hydrolase]]
[[Category: Hydrolase]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Jun 30 18:44:20 2008''

Revision as of 15:44, 30 June 2008

Image:1bb0.png

Template:STRUCTURE 1bb0

THROMBIN INHIBITORS WITH RIGID TRIPEPTIDYL ALDEHYDES

Template:ABSTRACT PUBMED 9724521

About this Structure

1BB0 is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.

Reference

Highly selective mechanism-based thrombin inhibitors: structures of thrombin and trypsin inhibited with rigid peptidyl aldehydes., Krishnan R, Zhang E, Hakansson K, Arni RK, Tulinsky A, Lim-Wilby MS, Levy OE, Semple JE, Brunck TK, Biochemistry. 1998 Sep 1;37(35):12094-103. PMID:9724521

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