1gmn

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Revision as of 22:45, 22 December 2014

CRYSTAL STRUCTURES OF NK1-HEPARIN COMPLEXES REVEAL THE BASIS FOR NK1 ACTIVITY AND ENABLE ENGINEERING OF POTENT AGONISTS OF THE MET RECEPTOR

Structural highlights

1gmn 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:	, ,
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

NK1 is a splice variant of the polypeptide growth factor HGF/SF, which consists of the N-terminal (N) and first kringle (K) domain and requires heparan sulfate or soluble heparin for activity. We describe two X-ray crystal structures of NK1-heparin complexes that define a heparin-binding site in the N domain, in which a major role is played by R73, with further contributions from main chain atoms of T61, K63 and G79 and the side chains of K60, T61, R76, K62 and K58. Mutagenesis experiments demonstrate that heparin binding to this site is essential for dimerization in solution and biological activity of NK1. Heparin also comes into contact with a patch of positively charged residues (K132, R134, K170 and R181) in the K domain. Mutation of these residues yields NK1 variants with increased biological activity. Thus, we uncover a complex role for heparan sulfate in which binding to the primary site in the N domain is essential for biological activity whereas binding to the K domain reduces activity. We exploit the interaction between heparin and the K domain site in order to engineer NK1 as a potent receptor agonist and suggest that dual (positive and negative) control may be a general mechanism of heparan sulfate-dependent regulation of growth factor activity.

Crystal structures of NK1-heparin complexes reveal the basis for NK1 activity and enable engineering of potent agonists of the MET receptor.,Lietha D, Chirgadze DY, Mulloy B, Blundell TL, Gherardi E EMBO J. 2001 Oct 15;20(20):5543-55. PMID:11597998^[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
↑ Lietha D, Chirgadze DY, Mulloy B, Blundell TL, Gherardi E. Crystal structures of NK1-heparin complexes reveal the basis for NK1 activity and enable engineering of potent agonists of the MET receptor. EMBO J. 2001 Oct 15;20(20):5543-55. PMID:11597998 doi:10.1093/emboj/20.20.5543

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/1gmn"

@@ Line 3: / Line 3: @@
 == Structural highlights ==
 <table><tr><td colspan='2'>[[1gmn]] 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=1GMN OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1GMN FirstGlance]. <br>
-</td></tr><tr><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=EPE:4-(2-HYDROXYETHYL)-1-PIPERAZINE+ETHANESULFONIC+ACID'>EPE</scene>, <scene name='pdbligand=IDS:2-O-SULFO-ALPHA-L-IDOPYRANURONIC+ACID'>IDS</scene>, <scene name='pdbligand=SGN:N,O6-DISULFO-GLUCOSAMINE'>SGN</scene><br>
+</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=EPE:4-(2-HYDROXYETHYL)-1-PIPERAZINE+ETHANESULFONIC+ACID'>EPE</scene>, <scene name='pdbligand=IDS:2-O-SULFO-ALPHA-L-IDOPYRANURONIC+ACID'>IDS</scene>, <scene name='pdbligand=SGN:N,O6-DISULFO-GLUCOSAMINE'>SGN</scene></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=1gmn FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1gmn OCA], [http://www.rcsb.org/pdb/explore.do?structureId=1gmn RCSB], [http://www.ebi.ac.uk/pdbsum/1gmn 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=1gmn FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1gmn OCA], [http://www.rcsb.org/pdb/explore.do?structureId=1gmn RCSB], [http://www.ebi.ac.uk/pdbsum/1gmn 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 36: / Line 36: @@
 </StructureSection>
 [[Category: Homo sapiens]]
-[[Category: Blundell, T L.]]
+[[Category: Blundell, T L]]
-[[Category: Chirgadze, D Y.]]
+[[Category: Chirgadze, D Y]]
-[[Category: Gherardi, E.]]
+[[Category: Gherardi, E]]
-[[Category: Lietha, D.]]
+[[Category: Lietha, D]]
-[[Category: Mulloy, B.]]
+[[Category: Mulloy, B]]
 [[Category: Hgf/sf]]
 [[Category: Hormone-growth factor complex]]
 [[Category: Hormone/growth factor]]

1gmn

From Proteopedia

Revision as of 22:45, 22 December 2014

CRYSTAL STRUCTURES OF NK1-HEPARIN COMPLEXES REVEAL THE BASIS FOR NK1 ACTIVITY AND ENABLE ENGINEERING OF POTENT AGONISTS OF THE MET RECEPTOR

Structural highlights

Disease

Function

Evolutionary Conservation

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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