1QBV

CRYSTAL STRUCTURE OF THROMBIN COMPLEXED WITH AN GUANIDINE-MIMETIC INHIBITOR

Summary for 1QBV

• Entry DOI: 10.2210/pdb1qbv/pdb
• Descriptor: THROMBIN (LIGHT CHAIN), THROMBIN (HEAVY CHAIN), Hirudin, ... (5 entities in total)
• Functional Keywords: thrombin, inhibitor, 3dp, hydrolase, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Homo sapiens (human); More
• Cellular location: Secreted, extracellular space: P00734 P00734; Secreted: P28504
• Total number of polymer chains: 3
• Total formula weight: 35749.75

Authors

Bone, R.,Lu, T.,Illig, C.R.,Soll, R.M.,Spurlino, J.C. (deposition date: 1999-04-27, release date: 1999-10-27, Last modification date: 2024-11-20)

Primary citation

Bone, R.,Lu, T.,Illig, C.R.,Soll, R.M.,Spurlino, J.C.
Structural analysis of thrombin complexed with potent inhibitors incorporating a phenyl group as a peptide mimetic and aminopyridines as guanidine substitutes.
J.Med.Chem., 41:2068-2075, 1998

PubMed Abstract: The structure of the noncovalent complex of human alpha-thrombin with a nonpeptide inhibitor containing a central phenyl scaffold, N-[2-[5-methyl-3-(2-chlorophenylsulfonyloxy)phenoxy]ethyl]-N- methyl-4 -aminopyridine (1), has been determined to 2.20 A resolution. In addition, the thrombin-bound structures of two distinct amino acid-based inhibitors (3 and 4) containing different aminopyridine-derived guanidine mimetics have been determined. Each compound occupies the same region of the active site and projects an aminopyridine, a central hydrophobic group, and an aryl group, into the S1, S2, and aryl subsites on thrombin. Nonpeptide 1 forms only one direct intermolecular hydrogen bond to the thrombin active site and forms no hydrogen bonds to ordered molecules of solvent. Close contacts are observed between main-chain carbonyl groups on thrombin and the edges of the central phenyl and aminopyridine rings and the sulfonyl group of 1 such that atoms carrying opposite partial charges are juxtaposed. Aminopyridine groups in 3 and 4 also form close contacts with the edges of carbonyl groups on thrombin and are flexibly accommodated in the S1 subsite. Superposition of the bound conformations of 1 and D-Phe-Pro-amidobutylguanidine (2) revealed that the central phenyl scaffold of 1 substitutes for the peptide main chain of 2.

PubMed: 9622548
DOI: 10.1021/jm970796l

Experimental method

X-RAY DIFFRACTION (1.8 Å)