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Cited by 818Biomarkers in Disease MechanismsComplement system in diseasesProtein Structure and Dynamics

The physiological structure of human C-reactive protein and its complex with phosphocholine

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Thompson, Darren, Pepys, Mark B, Wood, Steve P·1999·Structure
DOI 10.1016/s0969-2126(99)80023-9
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Abstract

Background Human C-reactive protein (CRP) is the classical acute phase reactant, the circulating concentration of which rises rapidly and extensively in a cytokine-mediated response to tissue injury, infection and inflammation. Serum CRP values are routinely measured, empirically, to detect and monitor many human diseases. However, CRP is likely to have important host defence, scavenging and metabolic functions through its capacity for calcium-dependent binding to exogenous and autologous molecules containing phosphocholine (PC) and then activating the classical complement pathway. CRP may also have pathogenic effects and the recent discovery of a prognostic association between increased CRP production and coronary atherothrombotic events is of particular interest.Results The X-ray structures of fully calcified C-reactive protein, in the presence and absence of bound PC, reveal that although the subunit beta-sheet jellyroll fold is very similar to that of the homologous pentameric protein serum amyloid P component, each subunit is tipped towards the fivefold axis. PC is bound in a shallow surface pocket on each subunit, interacting with the two protein-bound calcium ions via the phosphate group and with Glu81 via the choline moiety. There is also an unexpected hydrophobic pocket adjacent to the ligand.Conclusions The structure shows how large ligands containing PC may be bound by CRP via a phosphate oxygen that projects away from the surface of the protein. Multipoint attachment of one planar face of the CRP molecule to a PC-bearing surface would leave available, on the opposite exposed face, the recognition sites for C1q, which have been identified by mutagenesis. This would enable CRP to target physiologically and/or pathologically significant complement activation. The hydrophobic pocket adjacent to bound PC invites the design of inhibitors of CRP binding that may have therapeutic relevance to the possible role of CRP in atherothrombotic events.

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  • In the proinflammatory phase, plasma CRP level is primarily an indicator of the severity of the primary insult, initiating innate immunity to clear tissue debris and microorganisms.

    “In this phase, plasma CRP level is primarily an indicator of the severity of the primary insult, initiating innate immunity to clear tissue debris and microorganisms and their products.148”

    From Hypoalbuminemia: Pathogenesis and Clinical Significance (2019) · cites this paper as [148]

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Authors
Thompson, D., Pepys, M. B., & Wood, S. P.
Affiliations
  • University of Southampton (GB)
  • Hammersmith Hospital (GB)
Corresponding author
Wood, Steve P
ORCID
Pepys, Mark B
Venue
Structure
Publisher
Elsevier BV
Published
1999-02
Volume
7
Issue
2
Pages
169-177
ISSN
0969-2126 (ISSN-L)
DOI
10.1016/s0969-2126(99)80023-9
OpenAlex
W1964336741
Cited by
818
References
58
Citations by year
2026: 16 · 2025: 25 · 2024: 32 · 2023: 51 · 2022: 47 · 2021: 62 · 2020: 53 · 2019: 43 · 2018: 47 · 2017: 32 · 2016: 40 · 2015: 47 · 2014: 44 · 2013: 38 · 2012: 34
FWCI
3.55
Type
journal article
Language
en
Open access
Licence
Locations
  • Structure (publishedVersion)
  • PubMed (publishedVersion)
  • UCL Discovery (University College London) (submittedVersion)
Funders
  • Wellcome Trust
  • Medical Research Council
Topics
  • Life Sciences › Immunology and Microbiology › Immunology › Biomarkers in Disease Mechanisms
  • Life Sciences › Immunology and Microbiology › Immunology › Complement system in diseases
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
Keywords
C-reactive protein, phosphorylcholine, protein-ligand binding, calcium-dependent binding, complement activation, atherothrombosis, acute phase response, X-ray crystal structure
MeSH terms
Serum Amyloid P-Component, Binding Sites, C-Reactive Protein, Calcium, Humans, Models, Molecular, Molecular Sequence Data, Phospholipids, Phosphorylcholine, Protein Binding, Protein Conformation, Complement C1q, Protein Structure, Secondary, Protein Structure, Tertiary, Crystallography, X-Ray

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