2PJ7

CRYSTAL STRUCTURE OF ACTIVATED PORCINE PANCREATIC CARBOXYPEPTIDASE B 2-(3-Aminomethyl-phenyl)-3-[((R)-1-benzenesulfonylamino-2-methyl-propyl)-hydroxy-phosphinoyl]-propionic acid COMPLEX

Summary for 2PJ7

• Entry DOI: 10.2210/pdb2pj7/pdb
• Related: 1Z5R 1ZG7 1ZG8 1ZG9 2PIY 2PIZ 2PJ0 2PJ1 2PJ2 2PJ3 2PJ4 2PJ5 2PJ6 2PJ8 2PJ9 2PJA 2PJB 2PJC
• Descriptor: Carboxypeptidase B, ZINC ION, (2S)-2-[3-(AMINOMETHYL)PHENYL]-3-[(R)-HYDROXY{(1R)-2-METHYL-1-[(PHENYLSULFONYL)AMINO]PROPYL}PHOSPHORYL]PROPANOIC ACID, ... (4 entities in total)
• Functional Keywords: carboxypeptidase b, exopeptidase, phosphinate based inhibitor, hydrolase
• Biological source: Sus scrofa (pig)
• Cellular location: Secreted: P09955
• Total number of polymer chains: 3
• Total formula weight: 105779.23

Authors

Adler, M.,Whitlow, M. (deposition date: 2007-04-15, release date: 2008-01-22, Last modification date: 2023-08-30)

Primary citation

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.
Structures of potent selective peptide mimetics bound to carboxypeptidase B.
Acta Crystallogr.,Sect.D, 64:149-157, 2008

PubMed Abstract: 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.

PubMed: 18219114
DOI: 10.1107/S0907444907057228

Experimental method

X-RAY DIFFRACTION (1.77 Å)