title: Interaction of serum amyloid P component with hexanoyl bis(D-proline) (CPHPC).
abstract: Under physiological conditions, the pentameric human plasma protein serum amyloid P component (SAP) binds hexanoyl bis(D-proline) (R-1-{6-[R-2-carboxy-pyrrolidin-1-yl]-6-oxo-hexanoyl}pyrrolidine-2-carboxylic acid; CPHPC) through its D-proline head groups in a calcium-dependent interaction. Cooperative effects in binding lead to a substantial enhancement of affinity. Five molecules of the bivalent ligand cross-link and stabilize pairs of SAP molecules, forming a decameric complex that is rapidly cleared from the circulation by the liver. Here, it is reported that X-ray analysis of the SAP complex with CPHPC and cadmium ions provides higher resolution detail of the interaction than is observed with calcium ions. Conformational isomers of CPHPC observed in solution by HPLC and by X-ray analysis are compared with the protein-bound form. These are discussed in relation to the development of CPHPC to provide SAP depletion for the treatment of amyloidosis and other indications.
authors.affiliation: Laboratory of Protein Crystallography, Wolfson Drug Discovery Unit, Centre for Amyloidosis and Acute Phase Proteins, Division of Medicine (Royal Free Campus), University College London, Rowland Hill Street, London NW3 2PF, England.
authors.forename: Simon E
authors.initials: SE
authors.lastname: Kolstoe
authors.affiliation: School of Biological Sciences, University of Southampton, Southampton SO17 1BJ, England.
authors.forename: Michelle C
authors.initials: MC
authors.lastname: Jenvey
authors.affiliation: Department of Life Sciences, Sir Ernst Chain Building, Imperial College London, London SW7 2AZ, England.
authors.forename: Alan
authors.initials: A
authors.lastname: Purvis
authors.affiliation: UK National Crystallography Service, School of Chemistry, University of Southampton, Southampton SO17 1BJ, England.
authors.forename: Mark E
authors.initials: ME
authors.lastname: Light
authors.affiliation: School of Life Sciences, University of Sussex, Falmer, Brighton BN1 9RQ, England.
authors.forename: Darren
authors.initials: D
authors.lastname: Thompson
authors.affiliation: Laboratory of Protein Crystallography, Wolfson Drug Discovery Unit, Centre for Amyloidosis and Acute Phase Proteins, Division of Medicine (Royal Free Campus), University College London, Rowland Hill Street, London NW3 2PF, England.
authors.forename: Peter
authors.initials: P
authors.lastname: Hughes
authors.affiliation: Laboratory of Protein Crystallography, Wolfson Drug Discovery Unit, Centre for Amyloidosis and Acute Phase Proteins, Division of Medicine (Royal Free Campus), University College London, Rowland Hill Street, London NW3 2PF, England.
authors.forename: Mark B
authors.initials: MB
authors.lastname: Pepys
authors.affiliation: Laboratory of Protein Crystallography, Wolfson Drug Discovery Unit, Centre for Amyloidosis and Acute Phase Proteins, Division of Medicine (Royal Free Campus), University College London, Rowland Hill Street, London NW3 2PF, England.
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Wood
mesh_terms: D002118:Calcium / Q000737:chemistry; D002151:Calorimetry; D002851:Chromatography, High Pressure Liquid; D018360:Crystallography, X-Ray; D011392:Proline / Q000031:analogs & derivatives / Q000737:chemistry*; D011487:Protein Conformation; D000683:Serum Amyloid P-Component / Q000737:chemistry*; D013816:Thermodynamics
chemical_list: D000683:Serum Amyloid P-Component; D011392:Proline; D002118:Calcium
keywords: CPHPC; amyloidosis; serum amyloid P component
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