9AVM

Crystal Structure of CARD9 coiled-coil K156-K214

Summary for 9AVM

• Entry DOI: 10.2210/pdb9avm/pdb
• Descriptor: Caspase recruitment domain-containing protein 9 (2 entities in total)
• Functional Keywords: adapter protein, immune system
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 4
• Total formula weight: 28556.48

Authors

Raymond, D.D.,Lemke, C.T. (deposition date: 2024-03-04, release date: 2025-03-12, Last modification date: 2026-04-29)

Primary citation

Rush, J.S.,Wertheimer, J.D.,Goldberg, S.D.,Raymond, D.,Szuchnicki, M.,Baltus, A.J.,Branson, J.,Stratton, C.F.,Patrick, A.N.,Steele, R.,Adhikary, S.,Del Rosario, A.,Liu, A.,Gomersall, N.J.,Chung, M.,Ranaghan, M.J.,Gu, X.,Brandt, M.,Cao, Z.,Bebenek, A.,Oliver, B.A.,Hoebe, K.,Szewczuk, L.M.,Venable, J.D.,Graham, D.B.,Towne, J.,Xavier, R.J.
Human genetics guides the discovery of CARD9 inhibitors with anti-inflammatory activity.
Cell, 189:1356-1370.e26, 2026

PubMed Abstract: Human genetic association studies highlight key genes involved in disease pathology, yet targets identified by these analyses often fall outside the traditional definitions of druggability. A rare truncated variant of the scaffold protein CARD9 is linked with protection from Crohn's disease, prompting us to pursue the development of inhibitors that might similarly modulate innate inflammatory responses. Using a phased approach, we first identified a ligandable site on CARD9 using a structurally diverse DNA-encoded library and defined this site in detail through X-ray crystallography. Building upon this, a subsequent ligand displacement screen identified additional molecules that uniquely engage CARD9 and prevent its assembly into scaffolds needed to nucleate a signalosome for downstream nuclear factor κB (NF-κB) induction. These inhibitors suppressed inflammatory cytokine production in dendritic cells and a humanized CARD9 mouse model. Collectively, this study illustrates a strategy for leveraging protective human genetic variants and chemical biology to tackle challenging targets for dampening inflammation.

PubMed: 41547356
DOI: 10.1016/j.cell.2025.12.013

Experimental method

X-RAY DIFFRACTION (1.79 Å)