1o5d
Dissecting and Designing Inhibitor Selectivity Determinants at the S1 site Using an Artificial Ala190 Protease (Ala190 uPA)
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OverviewOverview
A site-directed mutant of the serine protease urokinase-type plasminogen, activator (uPA), was produced to assess the contribution of the Ser190, side-chain to the affinity and selectivity of lead uPA inhibitors in the, absence of other differences present in comparisons of natural proteases., Crystallography and enzymology involving WT and Ala190 uPA were used to, calculate free energy binding contributions of hydrogen bonds involving, the Ser190 hydroxyl group (O(gamma)(Ser190)) responsible for the, remarkable selectivity of 6-halo-5-amidinoindole and, 6-halo-5-amidinobenzimidazole inhibitors toward uPA and against natural, Ala190 protease anti-targets. Crystal structures of uPA complexes of, novel, active site-directed arylguanidine and 2-aminobenzimidazole, inhibitors of WT uPA, together with associated K(i) values for WT and, Ala190 uPA, also indicate a significant role of Ser190 in the binding of, these classes of uPA inhibitors. Structures and associated K(i) values for, a lead inhibitor (CA-11) bound to uPA and to five other proteases, as well, as for other leads bound to multiple proteases, help reveal the features, responsible for the potency (K(i)=11nM) and selectivity of the remarkably, small inhibitor, CA-11. The 6-fluoro-5-amidinobenzimidzole, CA-11, is more, than 1000-fold selective against natural Ala190 protease anti-targets, and, more than 100-fold selective against other Ser190 anti-targets.
DiseaseDisease
Known diseases associated with this structure: Esophageal squamous cell carcinoma OMIM:[606551], Factor VII deficiency OMIM:[227500], Myocardial infarction, decreased susceptibility to OMIM:[227500]
About this StructureAbout this Structure
1O5D is a Protein complex structure of sequences from Homo sapiens with CR9 as ligand. Active as Coagulation factor VIIa, with EC number 3.4.21.21 Full crystallographic information is available from OCA.
ReferenceReference
Dissecting and designing inhibitor selectivity determinants at the S1 site using an artificial Ala190 protease (Ala190 uPA)., Katz BA, Luong C, Ho JD, Somoza JR, Gjerstad E, Tang J, Williams SR, Verner E, Mackman RL, Young WB, Sprengeler PA, Chan H, Mortara K, Janc JW, McGrath ME, J Mol Biol. 2004 Nov 19;344(2):527-47. PMID:15522303
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