9L21

cryo-EM structure of Vitamin K-dependent gamma-carboxylase complexed with factor IX

This is a non-PDB format compatible entry.

Summary for 9L21

• Entry DOI: 10.2210/pdb9l21/pdb
• EMDB information: 62765
• Descriptor: Vitamin K-dependent gamma-carboxylase, CHOLESTEROL HEMISUCCINATE, Coagulation factor IX, ... (11 entities in total)
• Functional Keywords: membrane protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 2
• Total formula weight: 89476.99

Authors

Yao, D.,Wu, K.,Lan, P. (deposition date: 2024-12-16, release date: 2025-10-22, Last modification date: 2026-05-06)

Primary citation

Wu, K.,Wang, Z.,Yao, D.,Li, S.,Wang, X.,Zhang, Y.,Cao, M.,Shen, Y.,Xing, S.,Wu, J.,Lei, M.,Lan, P.
Structural insight into bicarbonate-mediated carboxylation by human vitamin K-dependent carboxylase.
Nat Commun, 16:10480-10480, 2025

PubMed Abstract: Vitamin K-dependent (VKD) carboxylation, mediated by γ-glutamyl carboxylase (GGCX), is essential for the maturation of VKD proteins involved in critical physiological processes such as blood clotting, vascular calcification and bone metabolism. Here, we present cryo-electron microscopic structures of human GGCX alone and in complex with VKD proteins, vitamin K, and inhibitor anisindione. GGCX specifically recognizes diverse VKD substrates through high-affinity propeptide binding, while substrates like osteocalcin utilize a secondary exosite to enhance interaction. GGCX employs a conserved dipeptide anchoring mechanism that ensures processive carboxylation of glutamate residues. GGCX undergoes allosteric conformational changes that enable coordinated binding of vitamin K and glutamate substrates, facilitating the catalytic process. Additionally, we reveal a bicarbonate-mediated CO₂ capture mechanism that is conserved across bacterial and eukaryotic species, suggesting that this strategy for CO₂ utilization is both ancient and universal. Our findings lay the foundation for developing targeted anticoagulant drugs and innovative enzymatic CO₂ fixation strategies.

PubMed: 41290650
DOI: 10.1038/s41467-025-65488-3

Experimental method

ELECTRON MICROSCOPY (2.62 Å)