1ba8: Difference between revisions
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==Overview== | ==Overview== | ||
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 >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. | 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 >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. | ||
==Disease== | |||
Known diseases associated with this structure: Dysprothrombinemia OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=176930 176930]], Hyperprothrombinemia OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=176930 176930]], Hypoprothrombinemia OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=176930 176930]] | |||
==About this Structure== | ==About this Structure== | ||
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[[Category: hydrolase]] | [[Category: hydrolase]] | ||
''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Mon Nov | ''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Mon Nov 12 16:07:37 2007'' | ||
Revision as of 17:01, 12 November 2007
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THROMBIN INHIBITOR WITH A RIGID TRIPEPTIDYL ALDEHYDES
OverviewOverview
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 >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.
DiseaseDisease
Known diseases associated with this structure: Dysprothrombinemia OMIM:[176930], Hyperprothrombinemia OMIM:[176930], Hypoprothrombinemia OMIM:[176930]
About this StructureAbout this Structure
1BA8 is a Single protein structure of sequence from Homo sapiens with NAG and PMS as ligands. Active as Thrombin, with EC number 3.4.21.5 Structure known Active Site: CAT. Full crystallographic information is available from OCA.
ReferenceReference
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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