1YBW

Protease domain of HGFA with no inhibitor

Summary for 1YBW

• Entry DOI: 10.2210/pdb1ybw/pdb
• Descriptor: Hepatocyte growth factor activator precursor, 2-acetamido-2-deoxy-beta-D-glucopyranose (3 entities in total)
• Functional Keywords: hydrolase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 62212.72

Authors

Shia, S.,Stamos, J.,Kirchhofer, D.,Fan, B.,Wu, J.,Corpuz, R.T.,Santell, L.,Lazarus, R.A.,Eigenbrot, C. (deposition date: 2004-12-21, release date: 2005-02-15, Last modification date: 2024-10-30)

Primary citation

Shia, S.,Stamos, J.,Kirchhofer, D.,Fan, B.,Wu, J.,Corpuz, R.T.,Santell, L.,Lazarus, R.A.,Eigenbrot, C.
Conformational lability in serine protease active sites: structures of hepatocyte growth factor activator (HGFA) alone and with the inhibitory domain from HGFA inhibitor-1B.
J.Mol.Biol., 346:1335-1349, 2005

PubMed Abstract: 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.

PubMed: 15713485
DOI: 10.1016/j.jmb.2004.12.048

Experimental method

X-RAY DIFFRACTION (2.7 Å)