1o5b

File:1o5b.jpg

spinqualitylabelsall models 1o5b, resolution 1.85Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

Dissecting and Designing Inhibitor Selectivity Determinants at the S1 site Using an Artificial Ala190 Protease (Ala190 uPA)

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 disease associated with this structure: Alzheimer disease, late-onset, susceptibility to OMIM:[191840]

About this StructureAbout this Structure

1O5B is a Protein complex structure of sequences from Homo sapiens with and as ligands. Active as U-plasminogen activator, with EC number 3.4.21.73 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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