9BUX

Structure of GGCX-BGP-menaquinone-4 epoxide complex

This is a non-PDB format compatible entry.

Summary for 9BUX

• Entry DOI: 10.2210/pdb9bux/pdb
• EMDB information: 44912 44917 44923 44924
• Descriptor: Vitamin K-dependent gamma-carboxylase, Osteocalcin, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, ... (7 entities in total)
• Functional Keywords: vitamin k cycle, membrane protein, lyase-substrate complex, lyase/substrate
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 2
• Total formula weight: 102931.24

Authors

Wang, R.,Qi, X. (deposition date: 2024-05-17, release date: 2025-01-29, Last modification date: 2025-02-12)

Primary citation

Wang, R.,Chen, B.,Elghobashi-Meinhardt, N.,Tie, J.K.,Ayala, A.,Zhou, N.,Qi, X.
Structure and mechanism of vitamin-K-dependent gamma-glutamyl carboxylase.
Nature, 2025

PubMed Abstract: γ-Glutamyl carboxylase (GGCX) is the sole identified enzyme that uses vitamin K (VK) as a cofactor in humans. This protein catalyses the oxidation of VK hydroquinone to convert specific glutamate residues to γ-carboxyglutamate residues in VK-dependent proteins (VDPs), which are involved in various essential biological processes and diseases. However, the working mechanism of GGCX remains unclear. Here we report three cryogenic electron microscopy structures of human GGCX: in the apo state, bound to osteocalcin (a VDP) and bound to VK. The propeptide of the VDP binds to the lumenal domain of GGCX, which stabilizes transmembrane helices 6 and 7 of GGCX to create the VK-binding pocket. After binding of VK, residue Lys218 in GGCX mediates the oxidation of VK hydroxyquinone, which leads to the deprotonation of glutamate residues and the construction of γ-carboxyglutamate residues. Our structural observations and results from binding and cell biological assays and molecular dynamics simulations show that a cholesterol molecule interacts with the transmembrane helices of GGCX to regulate its protein levels in cells. Together, these results establish a link between cholesterol metabolism and VK-dependent pathways.

PubMed: 39880952
DOI: 10.1038/s41586-024-08484-9

Experimental method

ELECTRON MICROSCOPY (3.06 Å)