The Journal of Experimental Medicine
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Published online 3 April 2000.
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© The Rockefeller University Press, 0022-1007/2000/4/1105/ $5.00
The Journal of Experimental Medicine, Volume 191, Number 7, April 3, 2000 1105-1116

Original Article

Crystal Structure of the Cysteine-Rich Domain of Mannose Receptor Complexed with a Sulfated Carbohydrate Ligand

Yang Liua, Arthur J. Chirinoa,b, Ziva Misulovinc, Christine Leteuxd, Ten Feizid, Michel C. Nussenzweigc, and Pamela J. Bjorkmana,b

a Division of Biology 156-29, California Institute of Technology, Pasadena, California 91125
b Howard Hughes Medical Institute, California Institute of Technology, Pasadena, California 91125
c Department of Molecular Immunology and the Howard Hughes Medical Institute, The Rockefeller University, New York, New York 10021-6399
d Glycosciences Laboratory, Imperial College School of Medicine, Northwick Park Hospital, Harrow HA1 3UJ, United Kingdom
Division of Biology 156-29, California Institute of Technology, Pasadena, CA 91125.626-792-3683626-395-8350

bjorkman{at}cco.caltech.edu

The macrophage and epithelial cell mannose receptor (MR) binds carbohydrates on foreign and host molecules. Two portions of MR recognize carbohydrates: tandemly arranged C-type lectin domains facilitate carbohydrate-dependent macrophage uptake of infectious organisms, and the NH2-terminal cysteine-rich domain (Cys-MR) binds to sulfated glycoproteins including pituitary hormones. To elucidate the mechanism of sulfated carbohydrate recognition, we determined crystal structures of Cys-MR alone and complexed with 4-sulfated-N-acetylgalactosamine at 1.7 and 2.2 Å resolution, respectively. Cys-MR folds into an approximately three-fold symmetric β-trefoil shape resembling fibroblast growth factor. The sulfate portions of 4-sulfated-N-acetylgalactosamine and an unidentified ligand found in the native crystals bind in a neutral pocket in the third lobe. We use the structures to rationalize the carbohydrate binding specificities of Cys-MR and compare the recognition properties of Cys-MR with other β-trefoil proteins.

Key Words: β-trefoil protein • hydrogen bond network • multilectin receptor • pituitary hormones • sulfated GalNAc

Abbreviations used in this paper: 4-SO4-GalNAc, 4-sulfated-N-acetylgalactosamine; aFGF, acidic FGF; bFGF, basic FGF; CRD, carbohydrate-recognition domain; Cys-MR, cysteine-rich domain of the MR; FGF, fibroblast growth factor; MIRAS, multiple isomorphous replacement including anomalous scattering; MR, mannose receptor; SBP, sulfate binding protein.

Feinber, H., S. Park-Snyder, A.R. Kolatkar, C.T. Heise, M.E. Taylor, and W.I. Weis, manuscript submitted for publication.

© 2000 The Rockefeller University Press


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