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| | ==Structure of peptide P7, which binds Cdc42 and inhibits effector interactions.== | | ==Structure of peptide P7, which binds Cdc42 and inhibits effector interactions.== |
| - | <StructureSection load='6r28' size='340' side='right'caption='[[6r28]], [[NMR_Ensembles_of_Models | 35 NMR models]]' scene=''> | + | <StructureSection load='6r28' size='340' side='right'caption='[[6r28]]' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[6r28]] is a 1 chain structure. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6R28 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6R28 FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[6r28]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Synthetic_construct Synthetic construct]. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6R28 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6R28 FirstGlance]. <br> |
| - | </td></tr><tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=HCS:2-AMINO-4-MERCAPTO-BUTYRIC+ACID'>HCS</scene></td></tr> | + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=HCS:2-AMINO-4-MERCAPTO-BUTYRIC+ACID'>HCS</scene></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=6r28 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6r28 OCA], [http://pdbe.org/6r28 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6r28 RCSB], [http://www.ebi.ac.uk/pdbsum/6r28 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6r28 ProSAT]</span></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=6r28 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6r28 OCA], [https://pdbe.org/6r28 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6r28 RCSB], [https://www.ebi.ac.uk/pdbsum/6r28 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6r28 ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
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| | </StructureSection> | | </StructureSection> |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Mott, H R]] | + | [[Category: Synthetic construct]] |
| - | [[Category: Murphy, N P]] | + | [[Category: Mott HR]] |
| - | [[Category: Owen, D]] | + | [[Category: Murphy NP]] |
| - | [[Category: Cyclic peptide]] | + | [[Category: Owen D]] |
| - | [[Category: De novo protein]]
| + | |
| - | [[Category: Inhibitor]]
| + | |
| - | [[Category: Synthetic peptide]]
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| Structural highlights
Publication Abstract from PubMed
Aberrant Ras signalling drives 30% of cancers and inhibition of Rho family small-GTPase signalling has been shown to combat Ras-driven cancers. Here we present the discovery of a 16mer cyclic peptide that binds to Cdc42 with nanomolar affinity. Affinity maturation of this sequence has produced a panel of derived candidates with increased affinity and modulated specificity for other closely related small-GTPases. The structure of the tightest binding peptide was solved by NMR and its binding site on Cdc42 determined. Addition of a cell penetrating sequence allowed the peptides to access the cell interior and engage with their target(s), modulating signalling pathways. In Ras-driven cancer cell models, the peptides have an inhibitory effect on proliferation and show suppression of both invasion and motility. As such they represent promising candidates for Rho-family small GTPase inhibitors and therapeutics targeting Ras-driven cancers. Our data adds to the growing literature demonstrating that peptides are establishing their place in the biologics arm of drug discovery.
The discovery and maturation of peptide biologics targeting the small G protein Cdc42: a bioblockade for Ras-driven signalling.,Tetley GJN, Murphy NP, Bonetto S, Ivanova-Berndt G, Revell J, Mott HR, Cooley RN, Owen D J Biol Chem. 2020 Jan 20. pii: RA119.010077. doi: 10.1074/jbc.RA119.010077. PMID:31959628[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Tetley GJN, Murphy NP, Bonetto S, Ivanova-Berndt G, Revell J, Mott HR, Cooley RN, Owen D. The discovery and maturation of peptide biologics targeting the small G protein Cdc42: a bioblockade for Ras-driven signalling. J Biol Chem. 2020 Jan 20. pii: RA119.010077. doi: 10.1074/jbc.RA119.010077. PMID:31959628 doi:http://dx.doi.org/10.1074/jbc.RA119.010077
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