7TBA

Pentraxin - ligand complex

Summary for 7TBA

• Entry DOI: 10.2210/pdb7tba/pdb
• Descriptor: C-reactive protein, [3-(dibutylamino)propyl]phosphonic acid, CALCIUM ION (3 entities in total)
• Functional Keywords: inflammation, inhibitor, complex, immune system
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 20
• Total formula weight: 467989.96

Authors

Shing, K.S.C.T.,Morton, C.J.,Parker, M.W. (deposition date: 2021-12-21, release date: 2022-10-19, Last modification date: 2024-10-23)

Primary citation

Zeller, J.,Cheung Tung Shing, K.S.,Nero, T.L.,McFadyen, J.D.,Krippner, G.,Bogner, B.,Kreuzaler, S.,Kiefer, J.,Horner, V.K.,Braig, D.,Danish, H.,Baratchi, S.,Fricke, M.,Wang, X.,Kather, M.G.,Kammerer, B.,Woollard, K.J.,Sharma, P.,Morton, C.J.,Pietersz, G.,Parker, M.W.,Peter, K.,Eisenhardt, S.U.
A novel phosphocholine-mimetic inhibits a pro-inflammatory conformational change in C-reactive protein.
Embo Mol Med, 15:e16236-e16236, 2023

PubMed 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 template. X-ray crystallography revealed specific binding to the phosphocholine binding pockets of pCRP. We provide in vitro and in vivo proof-of-concept data demonstrating that the low molecular weight tool compound inhibits CRP-driven exacerbation of local inflammatory responses, while potentially preserving pathogen-defense functions of CRP. The inhibition of the conformational change generating pro-inflammatory CRP isoforms via phosphocholine-mimicking compounds represents a promising, potentially broadly applicable anti-inflammatory therapy.

PubMed: 36468184
DOI: 10.15252/emmm.202216236

Experimental method

X-RAY DIFFRACTION (3.5 Å)