Interaction of serum amyloid P component with hexanoyl bis(D-proline) (CPHPC)

Simon E. Kolstoe; Michelle C. Jenvey; Alan Purvis; Mark E. Light; Darren Thompson; Peter Hughes; Mark B. Pepys; Stephen P. Wood

doi:10.1107/S1399004714013455

Interaction of serum amyloid P component with hexanoyl bis(D-proline) (CPHPC)

Simon E. Kolstoe, Michelle C. Jenvey, Alan Purvis, Mark E. Light, Darren Thompson, Peter Hughes, Mark B. Pepys, Stephen P. Wood

Institute of Life Sciences and Healthcare

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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.

Original language	English
Pages (from-to)	2232-2240
Number of pages	9
Journal	Acta Crystallographica Section D
Volume	70
Issue number	8
Early online date	25 Jul 2014
DOIs	https://doi.org/10.1107/S1399004714013455
Publication status	Published - 1 Aug 2014

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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.",

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T1 - Interaction of serum amyloid P component with hexanoyl bis(D-proline) (CPHPC)

AU - Kolstoe, Simon E.

AU - Jenvey, Michelle C.

AU - Purvis, Alan

AU - Light, Mark E.

AU - Thompson, Darren

AU - Hughes, Peter

AU - Pepys, Mark B.

AU - Wood, Stephen P.

PY - 2014/8/1

Y1 - 2014/8/1

N2 - 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.

AB - 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.

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DO - 10.1107/S1399004714013455

M3 - Article

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SN - 1399-0047

VL - 70

SP - 2232

EP - 2240

JO - Acta Crystallographica Section D

JF - Acta Crystallographica Section D

IS - 8

ER -

Interaction of serum amyloid P component with hexanoyl bis(D-proline) (CPHPC)

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