Sandbox Reserved 1709: Difference between revisions
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=== Cap Domain === | === Cap Domain === | ||
[[Image: | [[Image:New membrane pic bundle.png|500 px|right|thumb|Figure 2. Orientation and interactions of the VKOR components cap domain, anchor domain, and helical tunnel within the cell membrane.]] | ||
A key part of VKOR is the function of the <scene name='90/904314/Cap_domain/6'>cap domain</scene>, which is located right above the helices of VKOR towards the intracellular part of the membrane. The cap has a helical shape and is located in close proximity to two other domains: the Anchor domain and beta hairpin. This combination of domains help to maintain the proper orientation in the membrane. The cap domain assists with activating Vitamin K as it induces the structural change of VKOR from the open conformation to the closed conformation upon substrate binding. Cap rearrangement and transition to the closed conformation initiates a domino effect through the [https://reader.elsevier.com/reader/sd/pii/S0021925820001386?token=9F8E1964241D20488CA55E035D35D9A5D650A7B3FDAD9A5579598A8DC00127539BE71CF1785B117102144AC1F41ABB6C&originRegion=us-east-1&originCreation=20220329001707/ catalytic mechanism]. The cap domain has critical interactions that stabilize the closed conformation including a <scene name='90/904314/Disulfide_bridge_stabilization/5'>disulfide bridge</scene> between C43 and C51, and polar interactions from D44. These interactions are broken up by reactive cysteines to induce different conformations and help facilitate this transition from the open conformation to the closed conformation during the activation of Vitamin K. | A key part of VKOR is the function of the <scene name='90/904314/Cap_domain/6'>cap domain</scene>, which is located right above the helices of VKOR towards the intracellular part of the membrane. The cap has a helical shape and is located in close proximity to two other domains: the Anchor domain and beta hairpin. This combination of domains help to maintain the proper orientation in the membrane. The cap domain assists with activating Vitamin K as it induces the structural change of VKOR from the open conformation to the closed conformation upon substrate binding. Cap rearrangement and transition to the closed conformation initiates a domino effect through the [https://reader.elsevier.com/reader/sd/pii/S0021925820001386?token=9F8E1964241D20488CA55E035D35D9A5D650A7B3FDAD9A5579598A8DC00127539BE71CF1785B117102144AC1F41ABB6C&originRegion=us-east-1&originCreation=20220329001707/ catalytic mechanism]. The cap domain has critical interactions that stabilize the closed conformation including a <scene name='90/904314/Disulfide_bridge_stabilization/5'>disulfide bridge</scene> between C43 and C51, and polar interactions from D44. These interactions are broken up by reactive cysteines to induce different conformations and help facilitate this transition from the open conformation to the closed conformation during the activation of Vitamin K. | ||
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=== Enzymatic Mechanism === | === Enzymatic Mechanism === | ||
[[Image: | [[Image:Ss_of_catalytic_mech.png|350 px| right| thumb | Figure 3. Mechanism of VKOR.]] | ||
The catalytic mechanism of VKOR is highly regulated and use <scene name='90/904314/Stage_4_catalytic_cycle/13'>four catalytic cysteine residues</scene> to activate Vitamin K necessary for blood coagulation. Figure 3 highlights these reactions that allow the substrate to be catalyzed to its active form through a series of 4 stages. The enzyme begins in <scene name='90/904314/Vkor_with_ko/1'>stage I</scene> in the open conformation with the cap domain open to allow substrate binding. Once a substrate binds, the cap domain transitions to the closed conformation when the C51-C132 disulfide bridge is attacked by reactive C43 located within the cap domain. This reaction forms a new disulfide bridge between C43 and C51 that pulls the cap domain over the binding pocket with the substrate bound to stabilize the closed conformation of VKOR. VKOR is now in <scene name='90/904314/Stage_2_catalytic_cycle/2'>stage II</scene>. Free cysteines are now available that provide strong stabilization of the closed conformation through interactions with the cap domain and the bound substrate. This puts the enzyme in <scene name='90/904314/Stage_3_catalytic_cycle/8'>stage III</scene>, where a free C135 is purposed to interact with the substrate within the binding pocket to stabilize it during activation. The catalytic free C132 located between the cap domain and helical tunnel is very reactive and will attack this C135 to break that interaction with the substrate and release the activated Vitamin K product into the blood stream to promote coagulation. Two very stable disulfide bridges between C43-C41 and C132-C135 are now present and VKOR is unbound, so the enzyme is in its final, unreactive <scene name='90/904314/Stage_4_catalytic_cycle/15'>stage IV</scene>. VKOR must undergo conformational changes to return to Stage 1 and reactivate its catalytic cysteines so that another molecule of Vitamin K can bind and be activated. | The catalytic mechanism of VKOR is highly regulated and use <scene name='90/904314/Stage_4_catalytic_cycle/13'>four catalytic cysteine residues</scene> to activate Vitamin K necessary for blood coagulation. Figure 3 highlights these reactions that allow the substrate to be catalyzed to its active form through a series of 4 stages. The enzyme begins in <scene name='90/904314/Vkor_with_ko/1'>stage I</scene> in the open conformation with the cap domain open to allow substrate binding. Once a substrate binds, the cap domain transitions to the closed conformation when the C51-C132 disulfide bridge is attacked by reactive C43 located within the cap domain. This reaction forms a new disulfide bridge between C43 and C51 that pulls the cap domain over the binding pocket with the substrate bound to stabilize the closed conformation of VKOR. VKOR is now in <scene name='90/904314/Stage_2_catalytic_cycle/2'>stage II</scene>. Free cysteines are now available that provide strong stabilization of the closed conformation through interactions with the cap domain and the bound substrate. This puts the enzyme in <scene name='90/904314/Stage_3_catalytic_cycle/8'>stage III</scene>, where a free C135 is purposed to interact with the substrate within the binding pocket to stabilize it during activation. The catalytic free C132 located between the cap domain and helical tunnel is very reactive and will attack this C135 to break that interaction with the substrate and release the activated Vitamin K product into the blood stream to promote coagulation. Two very stable disulfide bridges between C43-C41 and C132-C135 are now present and VKOR is unbound, so the enzyme is in its final, unreactive <scene name='90/904314/Stage_4_catalytic_cycle/15'>stage IV</scene>. VKOR must undergo conformational changes to return to Stage 1 and reactivate its catalytic cysteines so that another molecule of Vitamin K can bind and be activated. | ||
