4MRH

Crystal structure of the murine CD44 hyaluronan binding domain complex with a small molecule

4MRH の概要

• エントリーDOI: 10.2210/pdb4mrh/pdb
• 関連するPDBエントリー: 4MRD 4MRE 4MRF 4MRG 4NP2 4NP3
• 分子名称: CD44 antigen, 4-chloro-5-methylbenzene-1,2-diamine, DIMETHYL SULFOXIDE, ... (4 entities in total)
• 機能のキーワード: link module, cell receptor, hyaluronan binding, cell surface, cell adhesion-inhibitor complex, cell adhesion/inhibitor
• 由来する生物種: Mus musculus (mouse)
• 細胞内の位置: Cell membrane; Single-pass type I membrane protein: P15379
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 16959.35

構造登録者

Liu, L.K.,Finzel, B. (登録日: 2013-09-17, 公開日: 2014-04-30, 最終更新日: 2024-10-16)

主引用文献

Liu, L.K.,Finzel, B.C.
Fragment-Based Identification of an Inducible Binding Site on Cell Surface Receptor CD44 for the Design of Protein-Carbohydrate Interaction Inhibitors.
J.Med.Chem., 57:2714-2725, 2014

PubMed Abstract: Selective inhibitors of hyaluronan (HA) binding to the cell surface receptor CD44 will have value as probes of CD44-mediated signaling and have potential as therapeutic agents in chronic inflammation, cardiovascular disease, and cancer. Using biophysical binding assays, fragment screening, and crystallographic characterization of complexes with the CD44 HA binding domain, we have discovered an inducible pocket adjacent to the HA binding groove into which small molecules may bind. Iterations of fragment combination and structure-driven design have allowed identification of a series of 1,2,3,4-tetrahydroisoquinolines as the first nonglycosidic inhibitors of the CD44-HA interaction. The affinity of these molecules for the CD44 HA binding domain parallels their ability to interfere with CD44 binding to polymeric HA in vitro. X-ray crystallographic complexes of lead compounds are described and compared to a new complex with a short HA tetrasaccharide, to establish the tetrahydroisoquinoline pharmacophore as an attractive starting point for lead optimization.

PubMed: 24606063
DOI: 10.1021/jm5000276

実験手法

X-RAY DIFFRACTION (1.12 Å)