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5eel

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Revision as of 08:28, 26 December 2018

Grb7 SH2 with bicyclic peptide inhibitor

Structural highlights

5eel is a 12 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	, ,
NonStd Res:	,
Related:	5eeq
Gene:	GRB7 (HUMAN)
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

[GRB7_HUMAN] Adapter protein that interacts with the cytoplasmic domain of numerous receptor kinases and modulates down-stream signaling. Promotes activation of down-stream protein kinases, including STAT3, AKT1, MAPK1 and/or MAPK3. Promotes activation of HRAS. Plays a role in signal transduction in response to EGF. Plays a role in the regulation of cell proliferation and cell migration. Plays a role in the assembly and stability of RNA stress granules. Binds to the 5'UTR of target mRNA molecules and represses translation of target mRNA species, when not phosphorylated. Phosphorylation impairs RNA binding and promotes stress granule disassembly during recovery after cellular stress (By similarity).^[1] ^[2] ^[3] ^[4]

Publication Abstract from PubMed

The design of potent and specific peptide inhibitors to therapeutic targets is of enormous utility for both proof-of-concept studies and for the development of potential new therapeutics. Grb7 is a key signaling molecule in the progression of HER2 positive and triple negative breast cancers. Here we report the crystal structure of a stapled bicyclic peptide inhibitor G7-B1 in complex with the Grb7-SH2 domain. This revealed an unexpected binding mode of the peptide, in which the staple forms an alternative contact with the surface of the target protein. Based on this structural information, we designed a new series of bicyclic G7 peptides that progressively constrain the starting peptide, to arrive at the G7-B4 peptide that binds with an approximately 2-fold enhanced affinity to the Grb7-SH2 domain (KD = 0.83 muM) compared to G7-B1 and shows low affinity binding to Grb2-, Grb10- and Grb14-SH2 domains (KD > 100 muM). Furthermore, we determined the structure of the G7-B4 bicyclic peptide in complex with the Grb7-SH2 domain, both before and after ring closing metathesis to show that the closed staple is essential to the target interaction. The G7-B4 peptide represents an advance in the development of Grb7 inhibitors and is a classical example of structure aided inhibitor development.

Unexpected involvement of staple leads to redesign of selective bicyclic peptide inhibitor of Grb7.,Gunzburg MJ, Kulkarni K, Watson GM, Ambaye ND, Del Borgo MP, Brandt R, Pero SC, Perlmutter P, Wilce MC, Wilce JA Sci Rep. 2016 Jun 3;6:27060. doi: 10.1038/srep27060. PMID:27257138^[5]

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

References

↑ Han DC, Shen TL, Guan JL. Role of Grb7 targeting to focal contacts and its phosphorylation by focal adhesion kinase in regulation of cell migration. J Biol Chem. 2000 Sep 15;275(37):28911-7. PMID:10893408 doi:10.1074/jbc.M001997200
↑ Shen TL, Han DC, Guan JL. Association of Grb7 with phosphoinositides and its role in the regulation of cell migration. J Biol Chem. 2002 Aug 9;277(32):29069-77. Epub 2002 May 20. PMID:12021278 doi:10.1074/jbc.M203085200
↑ Han DC, Shen TL, Miao H, Wang B, Guan JL. EphB1 associates with Grb7 and regulates cell migration. J Biol Chem. 2002 Nov 22;277(47):45655-61. Epub 2002 Sep 9. PMID:12223469 doi:10.1074/jbc.M203165200
↑ Chu PY, Li TK, Ding ST, Lai IR, Shen TL. EGF-induced Grb7 recruits and promotes Ras activity essential for the tumorigenicity of Sk-Br3 breast cancer cells. J Biol Chem. 2010 Sep 17;285(38):29279-85. doi: 10.1074/jbc.C110.114124. Epub, 2010 Jul 9. PMID:20622016 doi:10.1074/jbc.C110.114124
↑ Gunzburg MJ, Kulkarni K, Watson GM, Ambaye ND, Del Borgo MP, Brandt R, Pero SC, Perlmutter P, Wilce MC, Wilce JA. Unexpected involvement of staple leads to redesign of selective bicyclic peptide inhibitor of Grb7. Sci Rep. 2016 Jun 3;6:27060. doi: 10.1038/srep27060. PMID:27257138 doi:http://dx.doi.org/10.1038/srep27060

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

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/5eel"

@@ Line 3: / Line 3: @@
 <StructureSection load='5eel' size='340' side='right' caption='[[5eel]], [[Resolution|resolution]] 2.47&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[5eel]] is a 12 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5EEL OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5EEL FirstGlance]. <br>
+<table><tr><td colspan='2'>[[5eel]] is a 12 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5EEL OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5EEL FirstGlance]. <br>
 </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=FMT:FORMIC+ACID'>FMT</scene>, <scene name='pdbligand=MLA:MALONIC+ACID'>MLA</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene></td></tr>
 <tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=73C:(2~{S})-2-AZANYL-3-BUTOXY-PROPANOIC+ACID'>73C</scene>, <scene name='pdbligand=AEA:(2-AMINO-2-CARBAMOYL-ETHYLSULFANYL)-ACETIC+ACID'>AEA</scene></td></tr>
 <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[5eeq|5eeq]]</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=5eel FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5eel OCA], [http://pdbe.org/5eel PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5eel RCSB], [http://www.ebi.ac.uk/pdbsum/5eel PDBsum]</span></td></tr>
+<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">GRB7 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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=5eel FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5eel OCA], [http://pdbe.org/5eel PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5eel RCSB], [http://www.ebi.ac.uk/pdbsum/5eel PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5eel ProSAT]</span></td></tr>
 </table>
 == Function ==
@@ Line 20: / Line 21: @@
 </div>
 <div class="pdbe-citations 5eel" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[Growth factor receptor-bound protein|Growth factor receptor-bound protein]]
 == References ==
 <references/>
 __TOC__
 </StructureSection>
+[[Category: Human]]
 [[Category: Gunzburg, M J]]
 [[Category: Watson, G M]]

5eel

From Proteopedia

Revision as of 08:28, 26 December 2018

Grb7 SH2 with bicyclic peptide inhibitor

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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