The crystal structure of human alpha-thrombin complexed with LY178550, a nonpeptidyl, active site-directed inhibitor
Research article published in Protein science : a publication of the Protein Society (1997)
Abstract
The crystal structure of human alpha-thrombin in complex with LY178550, a nonpeptidyl, active site-directed inhibitor, has been solved to 2.07 A resolution by the method of X-ray crystallography. The final model of the complex has a crystallographic R-value of 21.5% (Rfree = 23.1%) with 0.014 A and 2.4 degrees standard deviation from ideal bond lengths and angles, respectively. Well-defined electron density was observed for the inhibitor in the active site. The inhibitor binds to the active site in an L-shaped manner, mimicking the bound conformation of the tripeptide arginal series of thrombin inhibitors (Chirgadze NY et al., 1992, American Crystallographic Association Meeting 20: 116 [Abstr. PB311]). The basic amidine of LY178550 forms a salt bridge with Asp 189 within the specificity pocket, while the 4-benzylpiperidine side chain engages in a number of hydrophobic interactions at the S2 and S3 binding sites. The inhibitor does not interact in any fashion with the active site sequence Ser 214-Gly 216, as occurs with many of the inhibitors studied previously. The indole N-H of the inhibitor forms a hydrogen bond to the gamma-oxygen of the catalytic serine (Ser 195).
Abstract sourced from PubMed (NCBI) for the cited record. See the original publication for the authoritative version.
Summary
The crystal structure of human alpha-thrombin in complex with LY178550, a nonpeptidyl, active site-directed inhibitor, has been solved to 2.07 A resolution by the method of X-ray crystallography.
Why This Matters for Hirudotherapy
This X-ray crystallography study solved the structure of human alpha-thrombin in complex with LY178550, a nonpeptidyl active-site-directed inhibitor, to 2.07 angstrom resolution, detailing how the inhibitor's amidine forms a salt bridge with Asp189 in the specificity pocket and how its side chains engage the S2/S3 sites and hydrogen-bond to the catalytic Ser195. Its relevance to hirudotherapy is foundational and indirect: thrombin is the exact enzyme that the leech-derived anticoagulant hirudin inhibits, so atomic-level maps of the thrombin active site underpin the structure-based drug-discovery effort that the leech secretome helped inspire. The caveat is that this is a structural biochemistry study of a synthetic small-molecule inhibitor, not hirudin and not a leech product, and it reports no clinical or even cellular efficacy data; it is mechanistic context for thrombin inhibition rather than evidence about hirudotherapy itself.
Citation
The crystal structure of human alpha-thrombin complexed with LY178550, a nonpeptidyl, active site-directed inhibitor
Chirgadze NY et al. · Protein science : a publication of the Protein Society, 1997
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