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 2.07 A structure of human alpha-thrombin with the nonpeptidyl inhibitor LY178550 shows L-shaped active-site binding: its amidine forms a salt bridge with Asp189, the benzylpiperidine engages hydrophobic S2/S3 sites, and the indole N-H hydrogen-bonds to Ser195.
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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