5u06: Difference between revisions

From Proteopedia
Jump to navigation Jump to search
← Older edit
No edit summary
No edit summary
 
(One intermediate revision by the same user not shown)
Line 1: Line 1:


==Grb7-SH2 with bicyclic peptide inhibitor containing a pY mimetic==
==Grb7-SH2 with bicyclic peptide inhibitor containing a pY mimetic==
<StructureSection load='5u06' size='340' side='right' caption='[[5u06]], [[Resolution|resolution]] 2.10&Aring;' scene=''>
<StructureSection load='5u06' size='340' side='right'caption='[[5u06]], [[Resolution|resolution]] 2.10&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>[[5u06]] is a 8 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=5U06 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5U06 FirstGlance]. <br>
<table><tr><td colspan='2'>[[5u06]] is a 8 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=5U06 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5U06 FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=K:POTASSIUM+ION'>K</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]] 2.1&#8491;</td></tr>
<tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=1PA:4-(CARBOXYMETHYL)-L-PHENYLALANINE'>1PA</scene>, <scene name='pdbligand=48V:{[(2R)-2,3-DIAMINO-3-OXOPROPYL]SULFANYL}ACETIC+ACID'>48V</scene></td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=1PA:4-(CARBOXYMETHYL)-L-PHENYLALANINE'>1PA</scene>, <scene name='pdbligand=48V:{[(2R)-2,3-DIAMINO-3-OXOPROPYL]SULFANYL}ACETIC+ACID'>48V</scene>, <scene name='pdbligand=K:POTASSIUM+ION'>K</scene></td></tr>
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[5tyi|5tyi]], [[5u1q|5u1q]]</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=5u06 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5u06 OCA], [https://pdbe.org/5u06 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5u06 RCSB], [https://www.ebi.ac.uk/pdbsum/5u06 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5u06 ProSAT]</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=5u06 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5u06 OCA], [http://pdbe.org/5u06 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5u06 RCSB], [http://www.ebi.ac.uk/pdbsum/5u06 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5u06 ProSAT]</span></td></tr>
</table>
</table>
== Function ==
== Function ==
[[http://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>  
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Grb7 is a signaling protein with critical roles in tumor cell proliferation and migration and an established cancer therapeutic target. Here we explore chemical space to develop a new bicyclic peptide inhibitor, incorporating thioether and lactam linkers that binds with affinity (KD = 1.1 muM) and specificity to the Grb7-SH2 domain. Structural analysis of the Grb7-SH2/peptide complex revealed an unexpected binding orientation underlying the binding selectivity by this new scaffold. We further incorporated carboxymethylphenylalanine and carboxyphenylalanine phosphotyrosine mimetics and arrived at an optimized inhibitor that potently binds Grb7-SH2 (KD = 0.13 muM) under physiological conditions. X-ray crystal structures of these Grb7-SH2/peptide complexes reveal the structural basis for the most potent and specific inhibitors of Grb7 developed to date. Finally, we demonstrate that cell permeable versions of these peptides successfully block Grb7 mediated interactions in a breast cancer cell line, establishing the potential of these peptides in the development of novel therapeutics targeted to Grb7.
 
Discovery, Development, and Cellular Delivery of Potent and Selective Bicyclic Peptide Inhibitors of Grb7 Cancer Target.,Watson GM, Kulkarni K, Sang J, Ma X, Gunzburg MJ, Perlmutter P, Wilce MCJ, Wilce JA J Med Chem. 2017 Nov 22;60(22):9349-9359. doi: 10.1021/acs.jmedchem.7b01320. Epub, 2017 Nov 10. PMID:29083893<ref>PMID:29083893</ref>
 
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 5u06" style="background-color:#fffaf0;"></div>


==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: Human]]
[[Category: Homo sapiens]]
[[Category: Watson, G M]]
[[Category: Large Structures]]
[[Category: Wilce, J A]]
[[Category: Synthetic construct]]
[[Category: Grb7]]
[[Category: Watson GM]]
[[Category: Inhibitor]]
[[Category: Wilce JA]]
[[Category: Sh2 domain]]
[[Category: Signaling protein-inhibitor complex]]
[[Category: Signaling protein-peptide inhibitor complex]]
[[Category: Signalling]]

Latest revision as of 18:44, 6 March 2024

Grb7-SH2 with bicyclic peptide inhibitor containing a pY mimeticGrb7-SH2 with bicyclic peptide inhibitor containing a pY mimetic

Structural highlights

5u06 is a 8 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 2.1Å
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

5u06, resolution 2.10Å

Drag the structure with the mouse to rotate

Proteopedia Page Contributors and Editors (what is this?)Proteopedia Page Contributors and Editors (what is this?)

OCA
Retrieved from "https://proteopedia.openfox.io/wiki/index.php?title=5u06&oldid=4085207"