6ZRD
STRUCTURE OF THE HUMAN RBAP48 in complex with a macrocyclic peptide cyclized via a xylene linker attached to two cysteines
Summary for 6ZRD
| Entry DOI | 10.2210/pdb6zrd/pdb |
| Related | 6ZRC |
| Descriptor | Histone-binding protein RBBP4, macrocyclic peptide based on residues 659-672 of the metastasis-associated protein MTA1, 1,3,5-trimethylbenzene, ... (4 entities in total) |
| Functional Keywords | nurd, histone binding domain, wd40 domain, beta propeller, chromatin regulator, macrocyclic peptide, cell cycle |
| Biological source | Homo sapiens (Human) More |
| Total number of polymer chains | 4 |
| Total formula weight | 99023.62 |
| Authors | Vetter, I.R.,Porfetye, A.T. (deposition date: 2020-07-13, release date: 2020-12-02, Last modification date: 2024-11-13) |
| Primary citation | Hart, P.'.,Hommen, P.,Noisier, A.,Krzyzanowski, A.,Schuler, D.,Porfetye, A.T.,Akbarzadeh, M.,Vetter, I.R.,Adihou, H.,Waldmann, H. Structure Based Design of Bicyclic Peptide Inhibitors of RbAp48. Angew.Chem.Int.Ed.Engl., 60:1813-1820, 2021 Cited by PubMed Abstract: 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 K 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. PubMed: 33022847DOI: 10.1002/anie.202009749 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.5 Å) |
Structure validation
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