5m3a
Crystal structure of BRD4 BROMODOMAIN 1 IN COMPLEX WITH LIGAND 2
Structural highlights
DiseaseBRD4_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.[1] [2] FunctionBRD4_HUMAN Plays a role in a process governing chromosomal dynamics during mitosis (By similarity). Publication Abstract from PubMedFragment-based drug design exploits initial screening of low molecular weight compounds and their concomitant affinity improvement. The multitude of possible chemical modifications highlights the necessity to obtain structural information about the binding mode of a fragment. Herein we describe a novel NMR methodology - LOGSY-titration - that allows the determination of binding modes of low affinity binders in the protein-ligand interface and reveals suitable ligand positions for the addition of functional groups that either address or substitute protein-bound water - information of utmost importance for drug design. The particular benefit of the methodology and in contrast to conventional ligand-based methods is the independence of the molecular weight of the protein under study. The validity of the novel approach is demonstrated on two ligands interacting with Bromodomain 1 of Bromodomain containing protein 4, a prominent cancer target in pharmaceutical industry. Direct NMR Probing of Hydration Shells of Protein Ligand Interfaces and its Application to Drug Design.,Geist L, Mayer M, Cockcroft XL, Wolkerstorfer B, Kessler D, Engelhardt H, McConnell DB, Konrat R J Med Chem. 2017 Sep 14. doi: 10.1021/acs.jmedchem.7b00845. PMID:28910100[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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