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7BAG

C3b in complex with CP40

Summary for 7BAG
Entry DOI10.2210/pdb7bag/pdb
DescriptorComplement C3, Compstatin CP40, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, ... (9 entities in total)
Functional Keywordscomplement system, c3b, c3 convertase, inhibitor, immune system
Biological sourceHomo sapiens (Human)
More
Total number of polymer chains3
Total formula weight178330.76
Authors
Lamers, C.,Xue, X.,Smiesko, M.,van Son, H.,Wagner, B.,Sfyroera, G.,Gros, P.,Lambris, J.,Ricklin, D. (deposition date: 2020-12-15, release date: 2022-01-12, Last modification date: 2024-02-07)
Primary citationLamers, C.,Xue, X.,Smiesko, M.,van Son, H.,Wagner, B.,Berger, N.,Sfyroera, G.,Gros, P.,Lambris, J.D.,Ricklin, D.
Insight into mode-of-action and structural determinants of the compstatin family of clinical complement inhibitors.
Nat Commun, 13:5519-5519, 2022
Cited by
PubMed Abstract: With the addition of the compstatin-based complement C3 inhibitor pegcetacoplan, another class of complement targeted therapeutics have recently been approved. Moreover, compstatin derivatives with enhanced pharmacodynamic and pharmacokinetic profiles are in clinical development (e.g., Cp40/AMY-101). Despite this progress, the target binding and inhibitory modes of the compstatin family remain incompletely described. Here, we present the crystal structure of Cp40 complexed with its target C3b at 2.0-Å resolution. Structure-activity-relationship studies rationalize the picomolar affinity and long target residence achieved by lead optimization, and reveal a role for structural water in inhibitor binding. We provide explanations for the narrow species specificity of this drug class and demonstrate distinct target selection modes between clinical compstatin derivatives. Functional studies provide further insight into physiological complement activation and corroborate the mechanism of its compstatin-mediated inhibition. Our study may thereby guide the application of existing and development of next-generation compstatin analogs.
PubMed: 36127336
DOI: 10.1038/s41467-022-33003-7
PDB entries with the same primary citation
Experimental method
X-RAY DIFFRACTION (2 Å)
Structure validation

227561

数据于2024-11-20公开中

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