1ybw
From Proteopedia
(New page: 200px<br /> <applet load="1ybw" size="450" color="white" frame="true" align="right" spinBox="true" caption="1ybw, resolution 2.70Å" /> '''Protease domain of ...) |
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| - | [[Image:1ybw.gif|left|200px]]<br /> | + | [[Image:1ybw.gif|left|200px]]<br /><applet load="1ybw" size="350" color="white" frame="true" align="right" spinBox="true" |
| - | <applet load="1ybw" size=" | + | |
caption="1ybw, resolution 2.70Å" /> | caption="1ybw, resolution 2.70Å" /> | ||
'''Protease domain of HGFA with no inhibitor'''<br /> | '''Protease domain of HGFA with no inhibitor'''<br /> | ||
==Overview== | ==Overview== | ||
| - | Hepatocyte growth factor activator (HGFA) is a serine protease that | + | 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== | ==About this Structure== | ||
| - | 1YBW is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with NAG as [http://en.wikipedia.org/wiki/ligand ligand]. Full crystallographic information is available from [http:// | + | 1YBW is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with <scene name='pdbligand=NAG:'>NAG</scene> as [http://en.wikipedia.org/wiki/ligand ligand]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1YBW OCA]. |
==Reference== | ==Reference== | ||
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[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
[[Category: Single protein]] | [[Category: Single protein]] | ||
| - | [[Category: Corpuz, R | + | [[Category: Corpuz, R T.]] |
[[Category: Eigenbrot, C.]] | [[Category: Eigenbrot, C.]] | ||
[[Category: Fan, B.]] | [[Category: Fan, B.]] | ||
[[Category: Kirchhofer, D.]] | [[Category: Kirchhofer, D.]] | ||
| - | [[Category: Lazarus, R | + | [[Category: Lazarus, R A.]] |
[[Category: Santell, L.]] | [[Category: Santell, L.]] | ||
[[Category: Shia, S.]] | [[Category: Shia, S.]] | ||
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[[Category: hydrolase]] | [[Category: hydrolase]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 16:03:44 2008'' |
Revision as of 14:03, 21 February 2008
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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 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
Page seeded by OCA on Thu Feb 21 16:03:44 2008
Categories: Homo sapiens | Single protein | Corpuz, R T. | Eigenbrot, C. | Fan, B. | Kirchhofer, D. | Lazarus, R A. | Santell, L. | Shia, S. | Stamos, J. | Wu, J. | NAG | Hydrolase
