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Title: Ligand binding to pentraxins
Author: Mikolajek, Halina
ISNI:       0000 0001 3398 0066
Awarding Body: University of Southampton
Current Institution: University of Southampton
Date of Award: 2008
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The human pentraxin proteins, serum amyloid P component (SAP) and C-reactive protein (CRP) have emerged as potentially important targets in the treatment of amyloidosis and cardiovascular diseases respectively, although their normal physiological functions are unclear. Structurally highly conserved homologous proteins are present in common experimental animals such as the rat, mouse, rabbit and hamster but there are major differences from the human p,entraxins in their normal behaviour as acute phase proteins, fine ligand specificity and capacity to activate the complement system. . SAP binds to amyloid fibrils ofall types and may contribute to their formation, stabilisation and persistence. In order to extend our current knowledge ofligand recognition by SAP, the crystal structures ofSAP complexed to two ligands, Methylmalonic acid and Phosphatidylethanolamine, have been solved to 1.6 Aand 1.4Aresolution respectively. Since important biological functions ofproteins are often conserved among species, the structural differences between the rat and human pentraxins were investigated. The crystal structure ofrat SAP was solved to 2.2 Aresolution by molecular replacement. This pentameric structure displayed subtle differences in the electrostatic properties. It remains to be determined whether this has an effect on avid binding of SAP to DNA, a functional property ofh~manSAP still poorly understood. CRP, a pentraxin traditionally defined by its binding affinity for PC, was studied in complex with PE. The crystal structure ofthe CRP-PE complex at 2.7 Aresolution revealed that the nitrogen end ofPE dips further downwards into the hydrophobic pocket ofCRP than PC. CRP-mediated complement activation can exacerbate ischemic tissue injury in the heart as well as in the brain. Therefore, knowledge ofthe exact stoichiometry and the protein-protein interactions between CRP and C1q may aid the development ofsmall molecules capable ofdisrupting such protein-protein interactions. Purification of C1q has been achieved by ion-exchange chromatography and gel filtration from BPL paste. Crystallisation trials have been performed, however no crystals have been observed that contain the protein-protein complex.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available