11MH

Cryo-EM Structure of Human C3 Pro-Convertase bound to the Compstatin Analog Cp60, TED Conformation 2

Summary for 11MH

• Entry DOI: 10.2210/pdb11mh/pdb
• EMDB information: 75835
• Descriptor: Complement C3 beta chain, Complement C3b alpha' chain, Compstatin Cp60, ... (7 entities in total)
• Functional Keywords: complement system, c3, alternate pathway, c3 pro-convertase, c3b, factor b, compstatin, immune system
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 4
• Total formula weight: 261848.14

Authors

Herbine, K.,Lambris, J. (deposition date: 2026-03-04, release date: 2026-06-17)

Primary citation

Vogt, S.A.,Lander, A.J.,Herbine, K.,Umnyakova, E.,Felsch, J.,Aschwanden, R.,Hughes, S.E.,Schwardt, O.,Lill, M.A.,Smiesko, M.,Lambris, J.D.,Lamers, C.,Ricklin, D.
New Analogs of the Compstatin Family of Clinical Complement Inhibitors with Low Picomolar Target Affinity.
J.Med.Chem., 69:11592-11609, 2026

PubMed Abstract: Compstatin-class macrocyclic peptides have emerged as therapeutic complement modulators, with a PEGylated compstatin derivative being approved and sequence-optimized analogs with enhanced PK/PD properties showing clinical promise. By extending structure-activity relationship studies of compstatin, we identified a modification (V3I) that enhances the target affinity up to 30-fold. Analog Cp01-V3I represents the most potent proteinogenic compstatin ( = 20 nM), opening paths toward recombinant applications. Introducing the V3I modification into late-generation compstatin analogs yielded a low-picomolar-affinity derivative ( = 0.08 nM), termed Cp60, featuring potent complement inhibition in vitro. Cryogenic electron microscopy of the C3bB-Cp60 complex at 2.88 Å resolution confirmed the structural basis for enhanced target affinity and provided mechanistic insights. Lastly, we demonstrate that Cp60s ultralong target residence time enables diagnostic applications for detecting complement opsonins on biosurfaces. Collectively, this work highlights the importance of rigorous optimization of de novo peptide inhibitors to improve PK/PD properties and enable novel applications.

PubMed: 42063338
DOI: 10.1021/acs.jmedchem.6c00832

Experimental method

ELECTRON MICROSCOPY (3 Å)