2qj2

From Proteopedia

(Difference between revisions)

Revision as of 13:12, 19 January 2015

A Mechanistic Basis for Converting a Receptor Tyrosine Kinase Agonist to an Antagonist

Structural highlights

2qj2 is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:
Related:	1nk1, 1gp9, 1gmn, 1gmo, 1bht, 2hgf, 2qj4
Gene:	HGF, HPTA (Homo sapiens)
Resources:	FirstGlance, OCA, RCSB, PDBsum

Disease

[HGF_HUMAN] Defects in HGF are the cause of deafness autosomal recessive type 39 (DFNB39) [MIM:608265]. A form of profound prelingual sensorineural hearing loss. Sensorineural deafness results from damage to the neural receptors of the inner ear, the nerve pathways to the brain, or the area of the brain that receives sound information.^[1]

Function

[HGF_HUMAN] Potent mitogen for mature parenchymal hepatocyte cells, seems to be a hepatotrophic factor, and acts as a growth factor for a broad spectrum of tissues and cell types. Activating ligand for the receptor tyrosine kinase MET by binding to it and promoting its dimerization.^[2] ^[3]

Evolutionary Conservation

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

Publication Abstract from PubMed

Hepatocyte growth factor (HGF) activates the Met receptor tyrosine kinase by binding and promoting receptor dimerization. Here we describe a mechanistic basis for designing Met antagonists based on NK1, a natural variant of HGF containing the N-terminal and the first kringle domain. Through detailed biochemical and structural analyses, we demonstrate that both mouse and human NK1 induce Met dimerization via a conserved NK1 dimer interface. Mutations designed to alter the NK1 dimer interface abolish its ability to promote Met dimerization but retain full Met-binding activity. Importantly, these NK1 mutants act as Met antagonists by inhibiting HGF-mediated cell scattering, proliferation, branching, and invasion. The ability to separate the Met-binding activity of NK1 from its Met dimerization activity thus provides a rational basis for designing Met antagonists. This strategy of antagonist design may be applicable for other growth factor receptors by selectively abolishing the receptor activation ability but not the receptor binding of the growth factors.

A mechanistic basis for converting a receptor tyrosine kinase agonist to an antagonist.,Tolbert WD, Daugherty J, Gao C, Xie Q, Miranti C, Gherardi E, Woude GV, Xu HE Proc Natl Acad Sci U S A. 2007 Sep 11;104(37):14592-7. Epub 2007 Sep 5. PMID:17804794^[4]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Schultz JM, Khan SN, Ahmed ZM, Riazuddin S, Waryah AM, Chhatre D, Starost MF, Ploplis B, Buckley S, Velasquez D, Kabra M, Lee K, Hassan MJ, Ali G, Ansar M, Ghosh M, Wilcox ER, Ahmad W, Merlino G, Leal SM, Riazuddin S, Friedman TB, Morell RJ. Noncoding mutations of HGF are associated with nonsyndromic hearing loss, DFNB39. Am J Hum Genet. 2009 Jul;85(1):25-39. doi: 10.1016/j.ajhg.2009.06.003. Epub 2009 , Jul 2. PMID:19576567 doi:10.1016/j.ajhg.2009.06.003
↑ Stamos J, Lazarus RA, Yao X, Kirchhofer D, Wiesmann C. Crystal structure of the HGF beta-chain in complex with the Sema domain of the Met receptor. EMBO J. 2004 Jun 16;23(12):2325-35. Epub 2004 May 27. PMID:15167892 doi:10.1038/sj.emboj.7600243
↑ Tolbert WD, Daugherty-Holtrop J, Gherardi E, Vande Woude G, Xu HE. Structural basis for agonism and antagonism of hepatocyte growth factor. Proc Natl Acad Sci U S A. 2010 Jul 27;107(30):13264-9. Epub 2010 Jul 12. PMID:20624990 doi:10.1073/pnas.1005183107
↑ Tolbert WD, Daugherty J, Gao C, Xie Q, Miranti C, Gherardi E, Woude GV, Xu HE. A mechanistic basis for converting a receptor tyrosine kinase agonist to an antagonist. Proc Natl Acad Sci U S A. 2007 Sep 11;104(37):14592-7. Epub 2007 Sep 5. PMID:17804794

1 Structural highlights
2 Disease
3 Function
4 Evolutionary Conservation
5 Publication Abstract from PubMed
6 See Also
7 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/2qj2"

@@ Line 3: / Line 3: @@
 == Structural highlights ==
 <table><tr><td colspan='2'>[[2qj2]] is a 2 chain structure with 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=2QJ2 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2QJ2 FirstGlance]. <br>
-</td></tr><tr><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene><br>
+</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
-<tr><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1nk1|1nk1]], [[1gp9|1gp9]], [[1gmn|1gmn]], [[1gmo|1gmo]], [[1bht|1bht]], [[2hgf|2hgf]], [[2qj4|2qj4]]</td></tr>
+<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1nk1|1nk1]], [[1gp9|1gp9]], [[1gmn|1gmn]], [[1gmo|1gmo]], [[1bht|1bht]], [[2hgf|2hgf]], [[2qj4|2qj4]]</td></tr>
-<tr><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">HGF, HPTA ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens])</td></tr>
+<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">HGF, HPTA ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens])</td></tr>
-<tr><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2qj2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2qj2 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=2qj2 RCSB], [http://www.ebi.ac.uk/pdbsum/2qj2 PDBsum]</span></td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2qj2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2qj2 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=2qj2 RCSB], [http://www.ebi.ac.uk/pdbsum/2qj2 PDBsum]</span></td></tr>
-<table>
+</table>
 == Disease ==
 [[http://www.uniprot.org/uniprot/HGF_HUMAN HGF_HUMAN]] Defects in HGF are the cause of deafness autosomal recessive type 39 (DFNB39) [MIM:[http://omim.org/entry/608265 608265]]. A form of profound prelingual sensorineural hearing loss. Sensorineural deafness results from damage to the neural receptors of the inner ear, the nerve pathways to the brain, or the area of the brain that receives sound information.<ref>PMID:19576567</ref>
@@ Line 38: / Line 38: @@
 </StructureSection>
 [[Category: Homo sapiens]]
-[[Category: Daugherty, J.]]
+[[Category: Daugherty, J]]
-[[Category: Gao, C F.]]
+[[Category: Gao, C F]]
-[[Category: Gherardi, E.]]
+[[Category: Gherardi, E]]
-[[Category: Miranti, C.]]
+[[Category: Miranti, C]]
-[[Category: Tolbert, W D.]]
+[[Category: Tolbert, W D]]
-[[Category: Woude, G Vande.]]
+[[Category: Woude, G Vande]]
-[[Category: Xe, Q.]]
+[[Category: Xe, Q]]
-[[Category: Xu, H E.]]
+[[Category: Xu, H E]]
 [[Category: Hgf/sf]]
 [[Category: Hormone]]
 [[Category: Hormone/growth factor]]

2qj2

From Proteopedia

Revision as of 13:12, 19 January 2015

A Mechanistic Basis for Converting a Receptor Tyrosine Kinase Agonist to an Antagonist

Structural highlights

Disease

Function

Evolutionary Conservation

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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