4MRH: Crystal Structure Of The Murine Cd44 Hyaluronan Binding Domain Complex With A Small Molecule

Citation:
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.
PDB ID: 4MRHDownload
MMDB ID: 119743
PDB Deposition Date: 2013/9/17
Updated in MMDB: 2014/05
Experimental Method:
x-ray diffraction
Resolution: 1.12  Å
Source Organism:
Similar Structures:
Biological Unit for 4MRH: monomeric; determined by author and by software (PISA)
Molecular Components in 4MRH
Label Count Molecule
Protein (1 molecule)
1
Cd44 Antigen(Gene symbol: Cd44)
Molecule annotation
Chemicals (2 molecules)
1
1
2
1
* Click molecule labels to explore molecular sequence information.

Citing MMDB
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