Structural basis of ligand specificity in the human pentraxins, C-reactive protein and serum amyloid P component


Mikolajek, Halina, Kolstoe, Simon E., Pye, Valerie E., Mangione, Palma, Pepys, Mark B. and Wood, Stephen P. (2011) Structural basis of ligand specificity in the human pentraxins, C-reactive protein and serum amyloid P component Journal of Molecular Recognition, 24, (2), pp. 371-377. (doi:10.1002/jmr.1090). (PMID:21360619).

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Description/Abstract

The normal physiological roles of the phylogenetically conserved human plasma proteins C-reactive protein (CRP) and serum amyloid P component (SAP) are not known. Novel drugs targeting their ligand specificities are in clinical development as both proteins have significant pathophysiological effects, SAP in promoting amyloidosis and CRP in exacerbating ischemic injury. Both proteins bind to phosphoethanolamine and we show here that, under physiological conditions, phosphoethanolamine is bound with higher affinity by human SAP than by human CRP. An explanation is provided by X-ray crystal structures that show SAP residue Tyr74 allowing additional hydrophobic protein–ligand interactions compared with the equivalent Thr76 of CRP. Docking simulations show many more low energy positions for phosphoethanolamine bound by CRP than by SAP and are consistent with the crystallographic and functional binding results. These fundamental observations on structure–activity relationships will aid the design of improved pentraxin targeting drugs.

Item Type: Article
Digital Object Identifier (DOI): doi:10.1002/jmr.1090
ISSNs: 0952-3499 (print)
Keywords: pentraxins, myloidosis, c-reactive protein, serum amyloid p component
Subjects:
Organisations: Centre for Biological Sciences
ePrint ID: 337109
Date :
Date Event
25 February 2011e-pub ahead of print
March 2011Published
Date Deposited: 18 Apr 2012 11:25
Last Modified: 17 Apr 2017 17:18
Further Information:Google Scholar
URI: http://eprints.soton.ac.uk/id/eprint/337109

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