9BVL
Vitamin K-dependent gamma-carboxylase with factor X propeptide and glutamate-rich region and with vitamin K hydroquinone
This is a non-PDB format compatible entry.
Summary for 9BVL
| Entry DOI | 10.2210/pdb9bvl/pdb |
| EMDB information | 44936 |
| Descriptor | Vitamin K-dependent gamma-carboxylase, Factor X light chain, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, ... (6 entities in total) |
| Functional Keywords | ggcx, vkgc, vitamin k, vkcfd, hemophilia b, warfarin, carboxylation, blood coagulaton, calcium homeostasis, factor x, membrane protein, lyase-substrate complex, lyase/substrate |
| Biological source | Homo sapiens (human) More |
| Total number of polymer chains | 2 |
| Total formula weight | 96271.65 |
| Authors | |
| Primary citation | Cao, Q.,Ammerman, A.,Saimi, M.,Lin, Z.,Shen, G.,Chen, H.,Sun, J.,Chai, M.,Liu, S.,Hsu, F.F.,Krezel, A.M.,Gross, M.L.,Xu, J.,Garcia, B.A.,Liu, B.,Li, W. Molecular basis of vitamin-K-driven gamma-carboxylation at the membrane interface. Nature, 639:816-824, 2025 Cited by PubMed Abstract: The γ-carboxylation of glutamate residues enables Ca-mediated membrane assembly of protein complexes that support broad physiological functions including hemostasis, calcium homeostasis, immune response, and endocrine regulation. Modulating γ-carboxylation level provides prevalent treatments for hemorrhagic and thromboembolic diseases. This unique posttranslational modification requires vitamin K hydroquinone (KH) to drive highly demanding reactions catalyzed by the membrane-integrated γ-carboxylase (VKGC). To decipher underlying mechanisms, we determined cryo-electron microscopy structures of human VKGC in unbound form, with KH and four hemostatic and non-hemostatic proteins possessing propeptides and glutamate-rich domains in different carboxylation states. VKGC recognizes substrate proteins via knob-and-hole interactions with propeptides, thereby bringing tethered glutamate-containing segments for processive carboxylation within a large chamber that provides steric control. Propeptide binding also triggers a global conformational change to signal VKGC activation. Through sequential deprotonation and KH epoxidation, VKGC generates free hydroxide ion as an exceptionally strong base required to deprotonate the γ-carbon of glutamate for CO addition. The diffusion of this superbase, protected and guided by a sealed hydrophobic tunnel, elegantly resolves the challenge of coupling KH epoxidation to γ-carboxylation across the membrane interface. These structural insights and extensive functional experiments advance membrane enzymology and propel the development of novel treatments for γ-carboxylation disorders. PubMed: 39880037DOI: 10.1038/s41586-025-08648-1 PDB entries with the same primary citation |
| Experimental method | ELECTRON MICROSCOPY (3.4 Å) |
Structure validation
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