Journal article
A novel phosphocholine-mimetic inhibits a pro-inflammatory conformational change in C-reactive protein
J Zeller, KS Cheung Tung Shing, TL Nero, JD McFadyen, G Krippner, B Bogner, S Kreuzaler, J Kiefer, VK Horner, D Braig, H Danish, S Baratchi, M Fricke, X Wang, MG Kather, B Kammerer, KJ Woollard, P Sharma, CJ Morton, G Pietersz Show all
EMBO Molecular Medicine | Published : 2023
Abstract
C-reactive protein (CRP) is an early-stage acute phase protein and highly upregulated in response to inflammatory reactions. We recently identified a novel mechanism that leads to a conformational change from the native, functionally relatively inert, pentameric CRP (pCRP) structure to a pentameric CRP intermediate (pCRP*) and ultimately to the monomeric CRP (mCRP) form, both exhibiting highly pro-inflammatory effects. This transition in the inflammatory profile of CRP is mediated by binding of pCRP to activated/damaged cell membranes via exposed phosphocholine lipid head groups. We designed a tool compound as a low molecular weight CRP inhibitor using the structure of phosphocholine as a te..
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Awarded by Australian Nuclear Science and Technology Organisation
Funding Acknowledgements
This research was partly undertaken at the Australian Synchrotron, part of the Australian Nuclear Science and Technology Organization, and made use of the ACRF Detector on the MX2 beamline. We thank the beamline staff for their assistance. This work was supported by personal grants to SUE from the German Research Foundation (DFG) EI 866/1-1, EI 866/1-2, and EI 866/10-1 and by a seed grant from the Baker Department of Cardiometabolic Health, University of Melbourne. Funding from the Victorian Government Operational Infrastructure Support Scheme to St Vincent's Institute and the Baker Institute is acknowledged. JDM is a National Heart Foundation Future Fellow. MWP (APP1194263) and KP (APP1174098) are National Health and Medical Research Council (NHMRC) of Australia Research Leadership 3 investigators. SUE is a Heisenberg Professor of the DFG. Laser scanning microscopy equipment was provided by the DFG as an institutional grant (INST 39/1137-1FUGG). We thank the Australian Cancer Research Foundation for support of the some of the equipment used in this work. Open Access funding enabled and organized by Projekt DEAL.