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| | ==Grb2 SH2 complexed with a pTyr-Ac6c-Asn tripeptide== | | ==Grb2 SH2 complexed with a pTyr-Ac6c-Asn tripeptide== |
| - | <StructureSection load='4p9z' size='340' side='right' caption='[[4p9z]], [[Resolution|resolution]] 1.80Å' scene=''> | + | <StructureSection load='4p9z' size='340' side='right'caption='[[4p9z]], [[Resolution|resolution]] 1.80Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4p9z]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4P9Z OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4P9Z FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4p9z]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [https://en.wikipedia.org/wiki/Synthetic_construct Synthetic construct]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4P9Z OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4P9Z FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.8Å</td></tr> |
| - | <tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=02K:1-AMINOCYCLOHEXANECARBOXYLIC+ACID'>02K</scene>, <scene name='pdbligand=NH2:AMINO+GROUP'>NH2</scene>, <scene name='pdbligand=NMI:3-(1-METHYL-1H-INDOL-3-YL)PROPANOIC+ACID'>NMI</scene>, <scene name='pdbligand=PTR:O-PHOSPHOTYROSINE'>PTR</scene></td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=02K:1-AMINOCYCLOHEXANECARBOXYLIC+ACID'>02K</scene>, <scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=NH2:AMINO+GROUP'>NH2</scene>, <scene name='pdbligand=NMI:3-(1-METHYL-1H-INDOL-3-YL)PROPANOIC+ACID'>NMI</scene>, <scene name='pdbligand=PTR:O-PHOSPHOTYROSINE'>PTR</scene></td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3s8o|3s8o]], [[4p9v|4p9v]]</td></tr>
| + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4p9z FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4p9z OCA], [https://pdbe.org/4p9z PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4p9z RCSB], [https://www.ebi.ac.uk/pdbsum/4p9z PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4p9z ProSAT]</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=4p9z FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4p9z OCA], [http://pdbe.org/4p9z PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4p9z RCSB], [http://www.ebi.ac.uk/pdbsum/4p9z PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4p9z ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == 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> | + | [https://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> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | ==See Also== | | ==See Also== |
| - | *[[Growth factor receptor-bound protein|Growth factor receptor-bound protein]] | + | *[[Growth factor receptor-bound proteins 3D structures|Growth factor receptor-bound proteins 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Clements, J H]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Martin, S F]] | + | [[Category: Large Structures]] |
| - | [[Category: Cation-pi interaction]] | + | [[Category: Synthetic construct]] |
| - | [[Category: Grb2 sh2]] | + | [[Category: Clements JH]] |
| | + | [[Category: Martin SF]] |
| Structural highlights
4p9z is a 2 chain structure with sequence from Homo sapiens and Synthetic construct. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Method: | X-ray diffraction, Resolution 1.8Å |
| Ligands: | , , , , , , |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
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]
Publication Abstract from PubMed
In order to probe the energetics associated with a putative cation-pi interaction, thermodynamic parameters are determined for complex formation between the Grb2 SH2 domain and tripeptide derivatives of RCO-pTyr-Ac6c-Asn wherein the R group is varied to include different alkyl, cycloalkyl, and aryl groups. Although an indole ring is reputed to have the strongest interaction with a guanidinium ion, binding free energies, DeltaG degrees , for derivatives of RCO-pTyr-Ac6c-Asn bearing cyclohexyl and phenyl groups were slightly more favorable than their indolyl analog. Crystallographic analysis of two complexes reveals that test ligands bind in similar poses with the notable exception of the relative orientation and proximity of the phenyl and indolyl rings relative to an arginine residue of the domain. These spatial orientations are consistent with those observed in other cation-pi interactions, but there is no net energetic benefit to such an interaction in this biological system. Accordingly, although cation-pi interactions are well documented as important noncovalent forces in molecular recognition, the energetics of such interactions may be mitigated by other nonbonded interactions and solvation effects in protein-ligand associations.
Protein-ligand interactions: Probing the energetics of a putative cation-pi interaction.,Myslinski JM, Clements JH, Martin SF Bioorg Med Chem Lett. 2014 Jul 15;24(14):3164-7. doi: 10.1016/j.bmcl.2014.04.114., Epub 2014 May 9. PMID:24856058[7]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
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
- ↑ Myslinski JM, Clements JH, Martin SF. Protein-ligand interactions: Probing the energetics of a putative cation-pi interaction. Bioorg Med Chem Lett. 2014 Jul 15;24(14):3164-7. doi: 10.1016/j.bmcl.2014.04.114., Epub 2014 May 9. PMID:24856058 doi:http://dx.doi.org/10.1016/j.bmcl.2014.04.114
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