1si5: Difference between revisions
No edit summary |
No edit summary |
||
| Line 1: | Line 1: | ||
[[Image:1si5.jpg|left|200px]] | [[Image:1si5.jpg|left|200px]] | ||
'''Protease-like domain from 2-chain hepatocyte growth factor''' | {{Structure | ||
|PDB= 1si5 |SIZE=350|CAPTION= <scene name='initialview01'>1si5</scene>, resolution 2.53Å | |||
|SITE= | |||
|LIGAND= | |||
|ACTIVITY= | |||
|GENE= | |||
}} | |||
'''Protease-like domain from 2-chain hepatocyte growth factor''' | |||
==Overview== | ==Overview== | ||
| Line 10: | Line 19: | ||
==About this Structure== | ==About this Structure== | ||
1SI5 is a [ | 1SI5 is a [[Single protein]] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1SI5 OCA]. | ||
==Reference== | ==Reference== | ||
Structural and functional basis of the serine protease-like hepatocyte growth factor beta-chain in Met binding and signaling., Kirchhofer D, Yao X, Peek M, Eigenbrot C, Lipari MT, Billeci KL, Maun HR, Moran P, Santell L, Wiesmann C, Lazarus RA, J Biol Chem. 2004 Sep 17;279(38):39915-24. Epub 2004 Jun 24. PMID:[http:// | Structural and functional basis of the serine protease-like hepatocyte growth factor beta-chain in Met binding and signaling., Kirchhofer D, Yao X, Peek M, Eigenbrot C, Lipari MT, Billeci KL, Maun HR, Moran P, Santell L, Wiesmann C, Lazarus RA, J Biol Chem. 2004 Sep 17;279(38):39915-24. Epub 2004 Jun 24. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/15218027 15218027] | ||
[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
[[Category: Single protein]] | [[Category: Single protein]] | ||
| Line 28: | Line 37: | ||
[[Category: chymotrypsin homology]] | [[Category: chymotrypsin homology]] | ||
''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Mar 20 14:05:17 2008'' | ||
Revision as of 15:05, 20 March 2008
| |||||||
| , resolution 2.53Å | |||||||
|---|---|---|---|---|---|---|---|
| Coordinates: | save as pdb, mmCIF, xml | ||||||
Protease-like domain from 2-chain hepatocyte growth factor
OverviewOverview
Hepatocyte growth factor (HGF), a plasminogen-related growth factor, is the ligand for Met, a receptor tyrosine kinase implicated in development, tissue regeneration, and invasive tumor growth. HGF acquires signaling activity only upon proteolytic cleavage of single-chain HGF into its alpha/beta heterodimer, similar to zymogen activation of structurally related serine proteases. Although both chains are required for activation, only the alpha-chain binds Met with high affinity. Recently, we reported that the protease-like HGF beta-chain binds to Met with low affinity (Stamos, J., Lazarus, R. A., Yao, X., Kirchhofer, D., and Wiesmann, C. (2004) EMBO J. 23, 2325-2335). Here we demonstrate that the zymogen-like form of HGF beta also binds Met, albeit with 14-fold lower affinity than the protease-like form, suggesting optimal interactions result from conformational changes upon cleavage of the single-chain form. Extensive mutagenesis of the HGF beta region corresponding to the active site and activation domain of serine proteases showed that 17 of the 38 purified two-chain HGF mutants resulted in impaired cell migration or Met phosphorylation but no loss in Met binding. However, reduced biological activities were well correlated with reduced Met binding of corresponding mutants of HGF beta itself in assays eliminating dominant alpha-chain binding contributions. Moreover, the crystal structure of HGF beta determined at 2.53 A resolution provides a structural context for the mutagenesis data. The functional Met binding site is centered on the "active site region" including "triad" residues Gln(534) [c57], Asp(578) [c102], and Tyr(673) [c195] and neighboring "activation domain" residues Val(692), Pro(693), Gly(694), Arg(695), and Gly(696) [c214-c219]. Together they define a region that bears remarkable resemblance to substrate processing regions of serine proteases. Models of HGF-dependent Met receptor activation are discussed.
DiseaseDisease
Known diseases associated with this structure: Fibromatosis, gingival OMIM:[182530], Noonan syndrome 4 OMIM:[182530]
About this StructureAbout this Structure
1SI5 is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.
ReferenceReference
Structural and functional basis of the serine protease-like hepatocyte growth factor beta-chain in Met binding and signaling., Kirchhofer D, Yao X, Peek M, Eigenbrot C, Lipari MT, Billeci KL, Maun HR, Moran P, Santell L, Wiesmann C, Lazarus RA, J Biol Chem. 2004 Sep 17;279(38):39915-24. Epub 2004 Jun 24. PMID:15218027
Page seeded by OCA on Thu Mar 20 14:05:17 2008