9mqb

Vitamin K-dependent gamma-carboxylase with Osteocalcin (mutant) and vitamin K hydroquinone and calcium

spinqualitylabelsall models 9mqb, resolution 3.37Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 9mqb is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: Electron Microscopy, Resolution 3.37Å Ligands: 6PL, A1AVC, NAG Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease VKGC_HUMAN Pseudoxanthoma elasticum-like skin manifestations with retinitis pigmentosa;Hereditary combined deficiency of vitamin K-dependent clotting factors;Body skin hyperlaxity due to vitamin K-dependent coagulation factor deficiency. The disease is caused by variants affecting the gene represented in this entry. The disease is caused by variants affecting the gene represented in this entry. Function VKGC_HUMAN Mediates the vitamin K-dependent carboxylation of glutamate residues to calcium-binding gamma-carboxyglutamate (Gla) residues with the concomitant conversion of the reduced hydroquinone form of vitamin K to vitamin K epoxide (PubMed:17073445). Catalyzes gamma-carboxylation of various proteins, such as blood coagulation factors (F2, F7, F9 and F10), osteocalcin (BGLAP) or matrix Gla protein (MGP) (PubMed:17073445). Publication Abstract from PubMed The gamma-carboxylation state of osteocalcin determines its essential functions in bone mineralization or systemic metabolism and serves as a prominent biomarker for bone health and vitamin K nutrition. This post-translational modification of glutamate residues is catalyzed by the membrane-embedded vitamin K-dependent gamma-carboxylase (VKGC), which typically recognizes protein substrates through their tightly bound propeptide that triggers gamma-carboxylation. However, the osteocalcin propeptide exhibits negligible affinity for VKGC. To understand the underlying molecular mechanism, we determined the cryo-electron microscopy structures of VKGC with osteocalcin carrying a native propeptide or a high-affinity variant at different carboxylation states. The structures reveal a large chamber in VKGC that maintains uncarboxylated and partially carboxylated osteocalcin in partially unfolded conformations, allowing their glutamate-rich region and C-terminal helices to engage with VKGC at multiple sites. Binding of this mature region together with the low-affinity propeptide effectively stimulates VKGC activity, similar to high-affinity propeptides that differ only in closely fitting interactions. However, the low-affinity propeptide renders osteocalcin prone to undercarboxylation at low vitamin K levels, thereby serving as a discernible biomarker. Overall, our studies reveal the unique interaction of osteocalcin with VKGC and provide a framework for designing therapeutic strategies targeting osteocalcin-related bone and metabolic disorders. Structural insights into the vitamin K-dependent gamma-carboxylation of osteocalcin.,Cao Q, Fan J, Ammerman A, Awasthi S, Lin Z, Mierxiati S, Chen H, Xu J, Garcia BA, Liu B, Li W Cell Res. 2025 Oct;35(10):735-749. doi: 10.1038/s41422-025-01161-0. Epub 2025 Sep , 2. PMID:40890294 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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