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| | {{STRUCTURE_2piy| PDB=2piy | SCENE= }} | | {{STRUCTURE_2piy| PDB=2piy | SCENE= }} |
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| - | '''CRYSTAL STRUCTURE OF ACTIVATED PORCINE PANCREATIC CARBOXYPEPTIDASE B (S)-2-(3-Aminomethyl-phenyl)-3-{hydroxy-[(R)-2-methyl-1-(3-phenyl-propane-1-sulfonylamino)-propyl]-phosphinoyl}-propionic acid {ZK 528} COMPLEX'''
| + | ===CRYSTAL STRUCTURE OF ACTIVATED PORCINE PANCREATIC CARBOXYPEPTIDASE B (S)-2-(3-Aminomethyl-phenyl)-3-{hydroxy-[(R)-2-methyl-1-(3-phenyl-propane-1-sulfonylamino)-propyl]-phosphinoyl}-propionic acid {ZK 528} COMPLEX=== |
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| - | ==Overview==
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| - | This article reports the crystal structures of inhibitors of the functional form of thrombin-activatable fibrinolysis inhibitor (TAFIa). In vivo experiments indicate that selective inhibitors of TAFIa would be useful in the treatment of heart attacks. Since TAFIa rapidly degrades in solution, the homologous protein porcine pancreatic carboxypeptidase B (pp-CpB) was used in these crystallography studies. Both TAFIa and pp-CpB are zinc-based exopeptidases that are specific for basic residues. The final development candidate, BX 528, is a potent inhibitor of TAFIa (2 nM) and has almost no measurable effect on the major selectivity target, carboxypeptidase N. BX 528 was designed to mimic the tripeptide Phe-Val-Lys. A sulfonamide replaces the Phe-Val amide bond and a phosphinate connects the Val and Lys groups. The phosphinate also chelates the active-site zinc. The electrostatic interactions with the protein mimic those of the natural substrate. The primary amine in BX 528 forms a salt bridge to Asp255 at the base of the S1' pocket. The carboxylic acid interacts with Arg145 and the sulfonamide is hydrogen bonded to Arg71. Isopropyl and phenyl groups replace the side chains of Val and Phe, respectively. A series of structures are presented here that illustrate the evolution of BX 528 from thiol-based inhibitors that mimic a free C-terminal arginine. The first step in development was the replacement of the thiol with a phosphinate. This caused a precipitous drop in binding affinity. Potency was reclaimed by extending the inhibitors into the downstream binding sites for the natural substrate.
| + | The line below this paragraph, {{ABSTRACT_PUBMED_18219114}}, adds the Publication Abstract to the page |
| | + | (as it appears on PubMed at http://www.pubmed.gov), where 18219114 is the PubMed ID number. |
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| | + | {{ABSTRACT_PUBMED_18219114}} |
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| | ==About this Structure== | | ==About this Structure== |
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| | [[Category: Hydrolase]] | | [[Category: Hydrolase]] |
| | [[Category: Phosphinate based inhibitor]] | | [[Category: Phosphinate based inhibitor]] |
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Wed Jun 11 10:55:01 2008'' | + | |
| | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Jul 28 23:51:27 2008'' |
Revision as of 20:51, 28 July 2008
Template:STRUCTURE 2piy
CRYSTAL STRUCTURE OF ACTIVATED PORCINE PANCREATIC CARBOXYPEPTIDASE B (S)-2-(3-Aminomethyl-phenyl)-3-{hydroxy-[(R)-2-methyl-1-(3-phenyl-propane-1-sulfonylamino)-propyl]-phosphinoyl}-propionic acid {ZK 528} COMPLEX
Template:ABSTRACT PUBMED 18219114
About this Structure
2PIY is a Single protein structure of sequence from Sus scrofa. Full crystallographic information is available from OCA.
Reference
Structures of potent selective peptide mimetics bound to carboxypeptidase B., Adler M, Buckman B, Bryant J, Chang Z, Chu K, Emayan K, Hrvatin P, Islam I, Morser J, Sukovich D, West C, Yuan S, Whitlow M, Acta Crystallogr D Biol Crystallogr. 2008 Feb;64(Pt 2):149-57. Epub 2008, Jan 16. PMID:18219114
Page seeded by OCA on Mon Jul 28 23:51:27 2008
