9BVR

Vitamin K-dependent gamma-carboxylase with factor IX propeptide and partially carboxylated glutamate-rich region and with vitamin K hydroquinone and calcium

これはPDB形式変換不可エントリーです。

9BVR の概要

• エントリーDOI: 10.2210/pdb9bvr/pdb
• EMDBエントリー: 44942
• 分子名称: Vitamin K-dependent gamma-carboxylase, Coagulation factor IX, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, ... (6 entities in total)
• 機能のキーワード: ggcx, vkgc, vitamin k, vkcfd, hemophilia b, warfarin, carboxylation, blood coagulaton, calcium homeostasis, membrane protein, lyase-substrate complex, lyase/substrate
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 96281.64

構造登録者

Li, W.,Liu, B.,Cao, Q. (登録日: 2024-05-20, 公開日: 2025-01-22, 最終更新日: 2025-03-26)

主引用文献

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

PubMed Abstract: The γ-carboxylation of glutamate residues enables Ca-mediated membrane assembly of protein complexes that support broad physiological functions, including haemostasis, calcium homeostasis, immune response and endocrine regulation. Modulating γ-carboxylation levels provides prevalent treatments for haemorrhagic and thromboembolic diseases. This unique post-translational modification requires vitamin K hydroquinone (KH) to drive highly demanding reactions catalysed by the membrane-integrated γ-carboxylase (VKGC). Here, to decipher the underlying mechanisms, we determined cryo-electron microscopy structures of human VKGC in unbound form, with KH and four haemostatic and non-haemostatic proteins possessing propeptides and glutamate-rich domains in different carboxylation states. VKGC recognizes substrate proteins through 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 a free hydroxide ion as an exceptionally strong base that is 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 treatments for γ-carboxylation disorders.

PubMed: 39880037
DOI: 10.1038/s41586-025-08648-1

実験手法

ELECTRON MICROSCOPY (3.5 Å)