THREE DIMENSIONAL STRUCTURE OF HUMAN C-REACTIVE PROTEIN. Trevor J. Greenhough^*, Graham M.T. Cheetham¹, David Holden, Dean A.A. Myles, William G. Turnell^1,2, John E. Volanakis³, Mark B. Pepys², Anne C. Bloomer¹ and Annette K. Shrive, Dept. of Physics, Keele University, Keele, Staffs, ST5 5BG, UK. ¹MRC Laboratory of Molecular Biology, Hills Road, Cambridge CB2 2QH, UK. ²Immunological Medicine Unit, Dept. of Medicine, Royal Postgraduate Medical School, Hammersmith Hospital, London W12 0NN, UK. ³Division of Clinical Immunology and Rheumatology, Dept. of Medicine, University of Alabama in Birmingham, Birmingham, Alabama 35294 USA, * and CCLRC Daresbury Laboratory, Warrington WA4 4AD, UK

Human C-reactive protein (CRP), first discovered in 1930 and the subject of intense clinical interest ever since, is a trace plasma protein that is expressed rapidly and dramatically as part of the acute phase response to infection or injury. The structure contains a remarkable crystal contact, where the Ca binding loop including Glu147 from one protomer (Type II) coordinates into the Ca site of a (Type I) protomer in a symmetry related pentamer, revealing the probable mode of binding of the principal ligand phosphocholine (PC) and providing information concerning conformational changes associated with calcium binding. The Glu147-Phe146 dipeptide from this loosely associated 140-150 loop mimics phosphate-choline binding, mediated through calcium and a hydrophobic pocket centered on Phe66, in the accepting Type I protomer, with Glu81 suitably positioned to interact with the choline group. The movement of the loop results in the loss of calcium in the donating Type II protomer where large concerted movements of the structure, involving residues 43-48, 67-72 and 85-91, are seen. A striking structural cleft, on the pentameric face opposite to the PC binding site, suggests an important functional role, perhaps in complement activation. There are significant conformational differences from SAP, both at the tertiary and molecular levels. The structure provides insights into the molecular mechanisms by which this highly conserved plasma protein, for which no polymorphism or deficiency state is known, may exert its biological role.