Crystal structure of a decameric complex of human serum amyloid P component with bound dAMP.
Serum amyloid P component (SAP) is a glycoprotein that binds in a calcium-dependent fashion to a variety of ligands including other proteins, glycosaminoglycans and DNA. SAP is universally associated with the amyloid deposits in all forms of amyloidoses including Alzheimer's disease. Small-molecule ligands that displace SAP from amyloid fibrils and thereby expose the fibrils to proteolytic clearance mechanisms hold potential as drugs for the prevention and treatment of amyloidosis. We have carried out a screen for novel SAP ligands and have identified 2'-deoxyadenosine-5'-monophosphate (dAMP) as a ligand. The crystal structure of the SAP-dAMP complex determined at 2.8 A resolution (R = 0.232, R(free) = 0.252) reveals a decamer in which all interactions between SAP pentamers are mediated by the ligand. The stability of the decamer in solution has been demonstrated by gel filtration chromatography. The two calcium ions of SAP are bridged by the dAMP phosphate group and five hydrogen bonds are formed between the protein and the ligand, including specific interactions made by the adenine base. This mode of dAMP binding is not compatible with the nucleotide being part of double-helical DNA. The SAP-dAMP decamer is stabilized mainly by base-stacking of adjacent ligand molecules and possibly by electrostatic interactions involving the dAMP phosphate groups; decamerization buries 1000 A2 (2.6%) of the pentamer solvent-accessible surface. Ligand-induced decamerization of SAP, which utilizes the high cooperativity of a multiple-site interaction, may be a strategy to overcome the problems for drug design associated with the rather modest affinities of SAP for small-molecule ligands.
Hohenester
E
E
Department of Crystallography, Birkbeck College, University of London, UK.
Hutchinson
W L
WL
Pepys
M B
MB
Wood
S P
SP
D003196:Computer Graphics; D018360:Crystallography, X-Ray; D003838:Deoxyadenine Nucleotides / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D008024:Ligands; D000683:Serum Amyloid P-Component / Q000737:chemistry* / Q000378:metabolism
D003838:Deoxyadenine Nucleotides; D008024:Ligands; D000683:Serum Amyloid P-Component; C012873:2'-deoxy-5'-adenosine monophosphate