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1jyq

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Revision as of 15:18, 24 December 2014

Xray Structure of Grb2 SH2 Domain Complexed with a Highly Affine Phospho Peptide

Structural highlights

1jyq is a 4 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
NonStd Res:	, ,
Related:	1jyr, 1jyu
Resources:	FirstGlance, OCA, RCSB, PDBsum

Function

[GRB2_HUMAN] Adapter protein that provides a critical link between cell surface growth factor receptors and the Ras signaling pathway.^[1] ^[2] ^[3] Isoform 2 does not bind to phosphorylated epidermal growth factor receptor (EGFR) but inhibits EGF-induced transactivation of a RAS-responsive element. Isoform 2 acts as a dominant negative protein over GRB2 and by suppressing proliferative signals, may trigger active programmed cell death.^[4] ^[5] ^[6]

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

The activation of growth factor receptors induces phosphorylation of tyrosine residues in its C-terminal part, creating binding sites for SH2 domain-containing proteins. Grb2 is a protein that recruits Sos, the exchange factor for Ras. Recruitment of Sos allows for Ras activation and subsequent signal transmission. This promotes translocation of MAP kinases into the nucleus and activation of early transcription factors. Grb2, a 25 kDa protein, is composed of one SH2 domain surrounded by two SH3 domains. The SH2 domain of Grb2 binds to class II phosphotyrosyl peptides with the consensus sequence pYXNX. Thus, Grb2 is a good example of a bifunctional adaptor protein that brings proteins into close proximity, allowing signal transduction through proteins located in different compartments.To explore the interactions between Grb2 and phosphorylated ligands, we have solved the crystal structure of complexes between the Grb2-SH2 domain and peptides corresponding to Shc-derived sequences. Two structures are described: the Grb2-SH2 domain in complex with PSpYVNVQN at 1.5 A; and the Grb2-SH2 domain in complex with mAZ*-pY-(alphaMe)pY-N-NH2 pseudo-peptide, at 2 A. Both are compared to an unliganded SH2 structure determined at 2.7 A which, interestingly enough, forms a dimer through two swapping subdomains from two symmetry-related molecules. The nanomolar affinity of the mAZ-pY-(alphaMe)pY-N-NH2 pseudo-peptide for Grb2-SH2 is related to new interactions with non- conserved residues.The design of Grb2-SH2 domain inhibitors that prevent interaction with tyrosine kinase proteins or other adaptors like Shc or IRS1 should provide a means to interrupt the Ras signaling pathway. Newly synthesized pseudo-peptides exhibit nanomolar affinities for the Grb2-SH2 domain. It will then be possible to design new inhibitors with similar affinity and simpler chemical structures.

Crystal structures of the SH2 domain of Grb2: highlight on the binding of a new high-affinity inhibitor.,Nioche P, Liu WQ, Broutin I, Charbonnier F, Latreille MT, Vidal M, Roques B, Garbay C, Ducruix A J Mol Biol. 2002 Feb 1;315(5):1167-77. PMID:11827484^[7]

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

References

↑ Lowenstein EJ, Daly RJ, Batzer AG, Li W, Margolis B, Lammers R, Ullrich A, Skolnik EY, Bar-Sagi D, Schlessinger J. The SH2 and SH3 domain-containing protein GRB2 links receptor tyrosine kinases to ras signaling. Cell. 1992 Aug 7;70(3):431-42. PMID:1322798
↑ Fath I, Schweighoffer F, Rey I, Multon MC, Boiziau J, Duchesne M, Tocque B. Cloning of a Grb2 isoform with apoptotic properties. Science. 1994 May 13;264(5161):971-4. PMID:8178156
↑ Pao-Chun L, Chan PM, Chan W, Manser E. Cytoplasmic ACK1 interaction with multiple receptor tyrosine kinases is mediated by Grb2: an analysis of ACK1 effects on Axl signaling. J Biol Chem. 2009 Dec 11;284(50):34954-63. doi: 10.1074/jbc.M109.072660. Epub, 2009 Oct 8. PMID:19815557 doi:10.1074/jbc.M109.072660
↑ Lowenstein EJ, Daly RJ, Batzer AG, Li W, Margolis B, Lammers R, Ullrich A, Skolnik EY, Bar-Sagi D, Schlessinger J. The SH2 and SH3 domain-containing protein GRB2 links receptor tyrosine kinases to ras signaling. Cell. 1992 Aug 7;70(3):431-42. PMID:1322798
↑ Fath I, Schweighoffer F, Rey I, Multon MC, Boiziau J, Duchesne M, Tocque B. Cloning of a Grb2 isoform with apoptotic properties. Science. 1994 May 13;264(5161):971-4. PMID:8178156
↑ Pao-Chun L, Chan PM, Chan W, Manser E. Cytoplasmic ACK1 interaction with multiple receptor tyrosine kinases is mediated by Grb2: an analysis of ACK1 effects on Axl signaling. J Biol Chem. 2009 Dec 11;284(50):34954-63. doi: 10.1074/jbc.M109.072660. Epub, 2009 Oct 8. PMID:19815557 doi:10.1074/jbc.M109.072660
↑ Nioche P, Liu WQ, Broutin I, Charbonnier F, Latreille MT, Vidal M, Roques B, Garbay C, Ducruix A. Crystal structures of the SH2 domain of Grb2: highlight on the binding of a new high-affinity inhibitor. J Mol Biol. 2002 Feb 1;315(5):1167-77. PMID:11827484 doi:10.1006/jmbi.2001.5299

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

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/1jyq"

@@ Line 3: / Line 3: @@
 == Structural highlights ==
 <table><tr><td colspan='2'>[[1jyq]] is a 4 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=1JYQ OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1JYQ FirstGlance]. <br>
-</td></tr><tr><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=MAZ:FORMIC+ACID+3-AMINO-BENZYL+ESTER'>MAZ</scene>, <scene name='pdbligand=PTM:ALPHA-METHYL-O-PHOSPHOTYROSINE'>PTM</scene>, <scene name='pdbligand=PTR:O-PHOSPHOTYROSINE'>PTR</scene></td></tr>
+</td></tr><tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=MAZ:FORMIC+ACID+3-AMINO-BENZYL+ESTER'>MAZ</scene>, <scene name='pdbligand=PTM:ALPHA-METHYL-O-PHOSPHOTYROSINE'>PTM</scene>, <scene name='pdbligand=PTR:O-PHOSPHOTYROSINE'>PTR</scene></td></tr>
-<tr><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1jyr|1jyr]], [[1jyu|1jyu]]</td></tr>
+<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1jyr|1jyr]], [[1jyu|1jyu]]</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=1jyq FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1jyq OCA], [http://www.rcsb.org/pdb/explore.do?structureId=1jyq RCSB], [http://www.ebi.ac.uk/pdbsum/1jyq 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=1jyq FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1jyq OCA], [http://www.rcsb.org/pdb/explore.do?structureId=1jyq RCSB], [http://www.ebi.ac.uk/pdbsum/1jyq PDBsum]</span></td></tr>
-<table>
+</table>
+== Function ==
+[[http://www.uniprot.org/uniprot/GRB2_HUMAN GRB2_HUMAN]] Adapter protein that provides a critical link between cell surface growth factor receptors and the Ras signaling pathway.<ref>PMID:1322798</ref> <ref>PMID:8178156</ref> <ref>PMID:19815557</ref>   Isoform 2 does not bind to phosphorylated epidermal growth factor receptor (EGFR) but inhibits EGF-induced transactivation of a RAS-responsive element. Isoform 2 acts as a dominant negative protein over GRB2 and by suppressing proliferative signals, may trigger active programmed cell death.<ref>PMID:1322798</ref> <ref>PMID:8178156</ref> <ref>PMID:19815557</ref>
 == Evolutionary Conservation ==
 [[Image:Consurf_key_small.gif|200px|right]]
@@ Line 33: / Line 35: @@
 </StructureSection>
 [[Category: Homo sapiens]]
-[[Category: Broutin, I.]]
+[[Category: Broutin, I]]
-[[Category: Charbonnier, F.]]
+[[Category: Charbonnier, F]]
-[[Category: Ducruix, A.]]
+[[Category: Ducruix, A]]
-[[Category: Garbay, C.]]
+[[Category: Garbay, C]]
-[[Category: Latreille, M T.]]
+[[Category: Latreille, M T]]
-[[Category: Liu, W Q.]]
+[[Category: Liu, W Q]]
-[[Category: Nioche, P.]]
+[[Category: Nioche, P]]
-[[Category: Roques, B.]]
+[[Category: Roques, B]]
-[[Category: Vidal, M.]]
+[[Category: Vidal, M]]
 [[Category: Receptor binding]]
 [[Category: Regulatory]]
 [[Category: Signaling protein-peptide inhibitor complex]]
 [[Category: Signaling protein-signaling protein inhibitor]]

1jyq

From Proteopedia

Revision as of 15:18, 24 December 2014

Xray Structure of Grb2 SH2 Domain Complexed with a Highly Affine Phospho Peptide

Structural highlights

Function

Evolutionary Conservation

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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