6zrd
From Proteopedia
(Difference between revisions)
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| - | ==== | + | ==STRUCTURE OF THE HUMAN RBAP48 in complex with a macrocyclic peptide cyclized via a xylene linker attached to two cysteines== |
| - | <StructureSection load='6zrd' size='340' side='right'caption='[[6zrd]]' scene=''> | + | <StructureSection load='6zrd' size='340' side='right'caption='[[6zrd]], [[Resolution|resolution]] 2.50Å' scene=''> |
== Structural highlights == | == Structural highlights == | ||
| - | <table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id= OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol= FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[6zrd]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6ZRD OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6ZRD FirstGlance]. <br> |
| - | </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=6zrd FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6zrd OCA], [https://pdbe.org/6zrd PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6zrd RCSB], [https://www.ebi.ac.uk/pdbsum/6zrd PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6zrd ProSAT]</span></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]] 2.5Å</td></tr> |
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ACE:ACETYL+GROUP'>ACE</scene>, <scene name='pdbligand=NH2:AMINO+GROUP'>NH2</scene>, <scene name='pdbligand=SEZ:1,3,5-trimethylbenzene'>SEZ</scene></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=6zrd FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6zrd OCA], [https://pdbe.org/6zrd PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6zrd RCSB], [https://www.ebi.ac.uk/pdbsum/6zrd PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6zrd ProSAT]</span></td></tr> | ||
</table> | </table> | ||
| + | == Function == | ||
| + | [https://www.uniprot.org/uniprot/RBBP4_HUMAN RBBP4_HUMAN] Core histone-binding subunit that may target chromatin assembly factors, chromatin remodeling factors and histone deacetylases to their histone substrates in a manner that is regulated by nucleosomal DNA. Component of several complexes which regulate chromatin metabolism. These include the chromatin assembly factor 1 (CAF-1) complex, which is required for chromatin assembly following DNA replication and DNA repair; the core histone deacetylase (HDAC) complex, which promotes histone deacetylation and consequent transcriptional repression; the nucleosome remodeling and histone deacetylase complex (the NuRD complex), which promotes transcriptional repression by histone deacetylation and nucleosome remodeling; the PRC2/EED-EZH2 complex, which promotes repression of homeotic genes during development; and the NURF (nucleosome remodeling factor) complex.<ref>PMID:10866654</ref> | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | The scaffolding protein RbAp48 is part of several epigenetic regulation complexes and is overexpressed in a variety of cancers. In order to develop tool compounds for the study of RbAp48 function, we have developed peptide inhibitors targeting the protein-protein interaction interface between RbAp48 and the scaffold protein MTA1. Based on a MTA1-derived linear peptide with low micromolar affinity and informed by crystallographic analysis, a bicyclic peptide was developed that inhibits the RbAp48/MTA1 interaction with a very low nanomolar KD value of 8.56 nM, and which showed appreciable stability against cellular proteases. Design included exchange of a polar amide cyclization strategy to hydrophobic aromatic linkers enabling mono- and bicyclization by means of cysteine alkylation, which improved affinity by direct interaction of the linkers with a hydrophobic residue on RbAp48. Our results demonstrate that stepwise evolution of a structure-based design is a suitable strategy for inhibitor development targeting PPIs. | ||
| + | |||
| + | Structure based design of bicyclic peptide inhibitors of RbAp48.,Waldmann H, 't Hart P, Hommen P, Noisier A, Krzyzanowski A, Schuler D, Porfetye AT, Akbarzadeh M, Vetter IR, Adihou H Angew Chem Int Ed Engl. 2020 Oct 6. doi: 10.1002/anie.202009749. PMID:33022847<ref>PMID:33022847</ref> | ||
| + | |||
| + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
| + | </div> | ||
| + | <div class="pdbe-citations 6zrd" style="background-color:#fffaf0;"></div> | ||
| + | |||
| + | ==See Also== | ||
| + | *[[Retinoblastoma-binding protein 3D structures|Retinoblastoma-binding protein 3D structures]] | ||
| + | == References == | ||
| + | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
| + | [[Category: Homo sapiens]] | ||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
| - | [[Category: | + | [[Category: Porfetye AT]] |
| + | [[Category: Vetter IR]] | ||
Current revision
STRUCTURE OF THE HUMAN RBAP48 in complex with a macrocyclic peptide cyclized via a xylene linker attached to two cysteines
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