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5u1q

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Revision as of 08:20, 8 January 2020

Grb7-SH2 with bicyclic peptide inhibitor

Structural highlights

5u1q is a 8 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:	5tyi, 5u06
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

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^[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
↑ Watson GM, Kulkarni K, Sang J, Ma X, Gunzburg MJ, Perlmutter P, Wilce MCJ, Wilce JA. Discovery, Development, and Cellular Delivery of Potent and Selective Bicyclic Peptide Inhibitors of Grb7 Cancer Target. J Med Chem. 2017 Nov 22;60(22):9349-9359. doi: 10.1021/acs.jmedchem.7b01320. Epub, 2017 Nov 10. PMID:29083893 doi:http://dx.doi.org/10.1021/acs.jmedchem.7b01320

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/5u1q"

@@ Line 1: / Line 1: @@
 ==Grb7-SH2 with bicyclic peptide inhibitor==
-<StructureSection load='5u1q' size='340' side='right' caption='[[5u1q]], [[Resolution|resolution]] 2.10&Aring;' scene=''>
+<StructureSection load='5u1q' size='340' side='right'caption='[[5u1q]], [[Resolution|resolution]] 2.10&Aring;' scene=''>
 == Structural highlights ==
 <table><tr><td colspan='2'>[[5u1q]] 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=5U1Q OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5U1Q FirstGlance]. <br>
@@ Line 23: / Line 23: @@
 ==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/>
@@ Line 29: / Line 29: @@
 </StructureSection>
 [[Category: Human]]
+[[Category: Large Structures]]
 [[Category: Watson, G M]]
 [[Category: Wilce, J A]]

5u1q

From Proteopedia

Revision as of 08:20, 8 January 2020

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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