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Structure of the inflammatory homing receptor CD44 complexed with its pericellular matrix ligand hyaluronan.
Author(s) -
Jackson David Gerald,
Banerji Suneale,
Day Anthony,
Wright Alan,
Mahoney David,
Campbell Iain
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.5.a915-b
Subject(s) - chemistry , ligand (biochemistry) , biophysics , receptor , stereochemistry , biochemistry , biology
The hyaluronan receptor CD44 mediates cell adhesion/migration through tissue matrix during embryonic morphogenesis, tissue repair and leukocyte homing. However, despite their fundamental importance, the precise molecular details of CD44:hyaluronan interactions remain unknown. Here we have determined the crystal structure of the hyaluronan‐binding domain complexed with a hyaluronan octasaccharide. This identifies the binding surface as a shallow groove in the main link module lined by a cluster of predominantly hydrophobic residues (tyrosine, alanine and isoleucine) and two key arginines, that together co‐ordinate four sugars (GlcUA5‐GlcNAc8) of the bound octasaccharide via hydrogen bonds rather than aromatic sugar stacking or ionic interactions. Moreover, we show that the complex experiences a conformational shift within the binding groove that brings an essential arginine residue (Arg45) into contact with ligand. A number of other residues within the link extension previously implicated in ligand‐binding, make no apparent contacts with ligand. These data define a molecular interaction of fundamental importance to cell migration as well as providing the basis necessary for rational design of small molecule inhibitors for the treatment of inflammatory disease.