5eeq: Difference between revisions

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== Function ==
== Function ==
[https://www.uniprot.org/uniprot/GRB7_HUMAN 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).<ref>PMID:10893408</ref> <ref>PMID:12021278</ref> <ref>PMID:12223469</ref> <ref>PMID:20622016</ref>  
[https://www.uniprot.org/uniprot/GRB7_HUMAN 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).<ref>PMID:10893408</ref> <ref>PMID:12021278</ref> <ref>PMID:12223469</ref> <ref>PMID:20622016</ref>  
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== 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 &gt; 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<ref>PMID:27257138</ref>
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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<div class="pdbe-citations 5eeq" style="background-color:#fffaf0;"></div>


==See Also==
==See Also==

Latest revision as of 08:33, 17 April 2024

Grb7 SH2 with the G7-B1 bicyclic peptide inhibitorGrb7 SH2 with the G7-B1 bicyclic peptide inhibitor

Structural highlights

5eeq is a 4 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 1.6Å
Ligands:, ,
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]

See Also

References

  1. ↑ 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
  2. ↑ 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
  3. ↑ 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
  4. ↑ 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

5eeq, resolution 1.60Å

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OCA
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