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Title: Interaction of serum amyloid P component with hexanoyl bis(d-proline) (CPHPC)

Serum amyloid P component is a pentameric plasma glycoprotein that recognizes and binds to amyloid fibres in a calcium-dependent fashion and is likely to contribute to their deposition and persistence in vivo. Five molecules of the drug CPHPC avidly cross-link pairs of protein pentamers and the decameric complex is rapidly cleared in vivo. Crystal structures of the protein in complex with a bivalent drug and cadmium ions, which improve crystal quality, allow the definition of the preferred bound drug isomers. 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 relationmore » to the development of CPHPC to provide SAP depletion for the treatment of amyloidosis and other indications.« less
Authors:
 [1] ;  [2] ;  [3] ;  [2] ;  [4] ; ; ;  [1]
  1. University College London, Rowland Hill Street, London NW3 2PF (United Kingdom)
  2. University of Southampton, Southampton SO17 1BJ (United Kingdom)
  3. Imperial College London, London SW7 2AZ (United Kingdom)
  4. University of Sussex, Falmer, Brighton BN1 9RQ (United Kingdom)
Publication Date:
OSTI Identifier:
22347745
Resource Type:
Journal Article
Resource Relation:
Journal Name: Acta Crystallographica. Section D: Biological Crystallography; Journal Volume: 70; Journal Issue: Pt 8; Other Information: PMCID: PMC4118831; PMID: 25084341; PUBLISHER-ID: mn5064; OAI: oai:pubmedcentral.nih.gov:4118831; Copyright (c) Kolstoe et al. 2014; This is an open-access article distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original authors and source are cited.; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
Denmark
Language:
English
Subject:
75 CONDENSED MATTER PHYSICS, SUPERCONDUCTIVITY AND SUPERFLUIDITY; AFFINITY; CADMIUM IONS; CALCIUM; CALCIUM IONS; COOPERATIVES; CRYSTAL STRUCTURE; CRYSTALS; DEPOSITION; IN VIVO; INTERACTIONS; LIGANDS; LIVER; MOLECULES; PLASMA