1LHE

HUMAN ALPHA-THROMBIN COMPLEXED WITH AC-(D)PHE-PRO-BORO-N-BUTYL-AMIDINO-GLYCINE-OH

Summary for 1LHE

• Entry DOI: 10.2210/pdb1lhe/pdb
• Descriptor: ALPHA-THROMBIN, HIRUDIN, AC-(D)PHE-PRO-BORO-N-BUTYL-AMIDINO-GLYCINE-OH, ... (5 entities in total)
• Functional Keywords: blood coagulation, plasma, calcium-binding, glycoprotein, duplication, vitamin k, zymogen, gamma-carboxyglutamic acid, acute phase, liver, hydrolase, serine protease, kringle, disease mutation, complex (serine protease-inhibitor), complex (serine protease-inhibitor) complex, complex (serine protease/inhibitor)
• Biological source: Hirudo medicinalis (medicinal leech); More
• Cellular location: Secreted, extracellular space: P00734 P00734
• Total number of polymer chains: 3
• Total formula weight: 35804.62

Authors

Weber, P.C.,Lee, S.L.,Lewandowski, F.A.,Schadt, M.C.,Chang, C.H.,Kettner, C.A. (deposition date: 1994-12-27, release date: 1996-11-08, Last modification date: 2024-06-05)

Primary citation

Weber, P.C.,Lee, S.L.,Lewandowski, F.A.,Schadt, M.C.,Chang, C.W.,Kettner, C.A.
Kinetic and crystallographic studies of thrombin with Ac-(D)Phe-Pro-boroArg-OH and its lysine, amidine, homolysine, and ornithine analogs.
Biochemistry, 34:3750-3757, 1995

PubMed Abstract: The X-ray crystallographic structure of Ac-(D)Phe-Pro-boroArg-OH [DuP714, Ki = 0.04 nM; Kettner, C., Mersinger, L., & Knabb, R. (1990) J. Biol. Chem. 265, 18289] complexed with human alpha-thrombin shows the boron atom covalently bonded to the side-chain oxygen of the active site serine, Ser195. The boron adopts a nearly tetrahedral geometry, and the boronic acid forms a set of interactions with the protein that mimic the tetrahedral transition state of serine proteases. Contributions of the arginine side chain to inhibitor affinity were examined by synthesis of the ornithine, lysine, homolysine, and amidine analogs of DuP714. The basic groups interact with backbone carbonyl groups, water molecules, and an aspartic acid side chain (Asp189) located in the thrombin S1 specificity pocket. The variation in inhibition constant by 3 orders of magnitude appears to reflect differences in the energetics of interactions made with thrombin and differences in ligand flexibility in solution.(ABSTRACT TRUNCATED AT 250 WORDS)

PubMed: 7893672
DOI: 10.1021/bi00011a033

Experimental method

X-RAY DIFFRACTION (2.25 Å)