7AQT
NMR2 structure of BRD4-BD2 in complex with iBET-762
Summary for 7AQT
| Entry DOI | 10.2210/pdb7aqt/pdb |
| NMR Information | BMRB: 34566 |
| Descriptor | Bromodomain-containing protein 4, 2-[(4S)-6-(4-chlorophenyl)-8-methoxy-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl]-N-ethylacetamide (2 entities in total) |
| Functional Keywords | brd4, bd2, bromodomain, ibet-762, nmr2, oncoprotein |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 1 |
| Total formula weight | 13173.69 |
| Authors | Orts, J.,Torres, F.,Milbradt, A.G.,Walser, R. (deposition date: 2020-10-23, release date: 2022-03-02, Last modification date: 2024-06-19) |
| Primary citation | Torres, F.,Walser, R.,Kaderli, J.,Rossi, E.,Bobby, R.,Packer, M.J.,Sarda, S.,Walker, G.,Hitchin, J.R.,Milbradt, A.G.,Orts, J. NMR Molecular Replacement Provides New Insights into Binding Modes to Bromodomains of BRD4 and TRIM24. J.Med.Chem., 65:5565-5574, 2022 Cited by PubMed Abstract: Structure-based drug discovery (SBDD) largely relies on structural information from X-ray crystallography because traditional NMR structure calculation methods are too time consuming to be aligned with typical drug discovery timelines. The recently developed NMR molecular replacement (MR) method dramatically reduces the time needed to generate ligand-protein complex structures using published structures (apo or holo) of the target protein and treating all observed NOEs as ambiguous restraints, bypassing the laborious process of obtaining sequence-specific resonance assignments for the protein target. We apply this method to two therapeutic targets, the bromodomain of TRIM24 and the second bromodomain of BRD4. We show that the MR methodology can guide SBDD by rationalizing the observed SAR. We also demonstrate that new types of restraints and selective methyl labeling have the potential to dramatically reduce "time to structure" and extend the method to targets beyond the reach of traditional NMR structure elucidation. PubMed: 35357834DOI: 10.1021/acs.jmedchem.1c01703 PDB entries with the same primary citation |
| Experimental method | SOLUTION NMR |
Structure validation
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