32pp

CRYSTAL STRUCTURE OF BRD4 BD1 IN COMPLEX WITH Compound 9

spinqualitylabelsall models 32pp, resolution 1.44Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 32pp is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.44Å Ligands: A1KEP, EDO Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease BRD4_HUMAN Note=A chromosomal aberration involving BRD4 is found in a rare, aggressive, and lethal carcinoma arising in midline organs of young people. Translocation t(15;19)(q14;p13) with NUT which produces a BRD4-NUT fusion protein. Function BRD4_HUMAN Plays a role in a process governing chromosomal dynamics during mitosis (By similarity). Publication Abstract from PubMed Fragment-based drug design is heavily dependent on the optimization of initial low-affinity binders. Herein we introduce an approach that uses selective labeling of methyl groups in leucine and isoleucine side chains to directly probe methyl-pi contacts, one of the most prominent forms of interaction between proteins and small molecules. Using simple NMR chemical shift perturbation experiments with selected BRD4-BD1 binders, we find good agreement with a commonly used model of the ring-current effect as well as the overall interaction geometries extracted from the Protein Data Bank. By combining both interaction geometries and chemical shift calculations as fit quality criteria, we can position dummy aromatic rings into an AlphaFold model of the protein of interest. The proposed method can therefore provide medicinal chemists with important information about binding geometries of small molecules in fast and iterative matter, even in the absence of high-resolution experimental structures. Probing Protein-Ligand Methyl-pi Interaction Geometries through Chemical Shift Measurements of Selectively Labeled Methyl Groups.,Beier A, Platzer G, Hofurthner T, Ptaszek AL, Lichtenecker RJ, Geist L, Fuchs JE, McConnell DB, Mayer M, Konrat R J Med Chem. 2024 Jul 28. doi: 10.1021/acs.jmedchem.4c01128. PMID:39069741 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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