Crystal structure of protein C inhibitor provides insights into hormone binding and heparin activation.
Protein C inhibitor (PCI) is a member of the serpin family that has many biological functions. In blood it acts as a procoagulant, and, in the seminal vesicles, it is required for spermatogenesis. The activity of PCI is affected by heparin binding in a manner unique among the heparin binding serpins, and, in addition, PCI binds hydrophobic hormones with apparent specificity for retinoids. Here we present the 2.4 A crystallographic structure of reactive center loop (RCL) cleaved PCI. A striking feature of the structure is a two-turn N-terminal shortening of helix A, which creates a large hydrophobic pocket that docking studies indicate to be the retinoid binding site. On the basis of surface electrostatic properties, a novel mechanism for heparin activation is proposed.
Huntington
James A
JA
Department of Haematology, Division of Structural Medicine, University of Cambridge, Cambridge Institute for Medical Research, Wellcome Trust/MRC Building, Hills Road, CB2 2XY, Cambridge, United Kingdom. jah52@cam.ac.uk
Kjellberg
Margareta
M
Stenflo
Johan
J
D001665:Binding Sites; D018360:Crystallography, X-Ray; D006493:Heparin / Q000378:metabolism*; D011485:Protein Binding; D018046:Protein C Inhibitor / Q000737:chemistry* / Q000378:metabolism; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D012176:Retinoids / Q000378:metabolism*
D018046:Protein C Inhibitor; D012176:Retinoids; D006493:Heparin