1ybw

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Revision as of 18:11, 12 November 2007

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spinqualitylabelsall models 1ybw, resolution 2.70Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

Protease domain of HGFA with no inhibitor

Overview

Hepatocyte growth factor activator (HGFA) is a serine protease that, converts hepatocyte growth factor (HGF) into its active form. When, activated HGF binds its cognate receptor Met, cellular signals lead to, cell growth, differentiation, and migration, activities which promote, tissue regeneration in liver, kidney and skin. Intervention in the, conversion of HGF to its active form has the potential to provide, therapeutic benefit where HGF/Met activity is associated with, tumorigenesis. To help identify ways to moderate HGF/Met effects, we have, determined the molecular structure of the protease domain of HGFA. The, structure we determined, at 2.7 A resolution, with no pseudo-substrate or, inhibitor bound is characterized by an unconventional conformation of key, residues in the enzyme active site. In order to find whether this, apparently non-enzymatically competent arrangement would persist in the, presence of a strongly-interacting inhibitor, we also have determined, at, 2.6 A resolution, the X-ray structure of HGFA complexed with the first, Kunitz domain (KD1) from the physiological inhibitor hepatocyte growth, factor activator inhibitor 1B (HAI-1B). In this complex we observe a, rearranged substrate binding cleft that closely mirrors the cleft of other, serine proteases, suggesting an extreme conformational dynamism. We also, characterize the inhibition of 16 serine proteases by KD1, finding that, the previously reported enzyme specificity of the intact extracellular, region of HAI-1B resides in KD1 alone. We find that HGFA, matriptase, hepsin, plasma kallikrein and trypsin are potently inhibited, and use the, complex structure to rationalize the structural basis of these results.

About this Structure

1YBW is a Single protein structure of sequence from Homo sapiens with NAG as ligand. Full crystallographic information is available from OCA.

Reference

Conformational lability in serine protease active sites: structures of hepatocyte growth factor activator (HGFA) alone and with the inhibitory domain from HGFA inhibitor-1B., Shia S, Stamos J, Kirchhofer D, Fan B, Wu J, Corpuz RT, Santell L, Lazarus RA, Eigenbrot C, J Mol Biol. 2005 Mar 11;346(5):1335-49. Epub 2005 Jan 28. PMID:15713485

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