7BAG

C3b in complex with CP40

Summary for 7BAG

• Entry DOI: 10.2210/pdb7bag/pdb
• Descriptor: Complement C3, Compstatin CP40, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, ... (9 entities in total)
• Functional Keywords: complement system, c3b, c3 convertase, inhibitor, immune system
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 3
• Total formula weight: 178330.76

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 citation

Lamers, 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

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

Experimental method

X-RAY DIFFRACTION (2 Å)