Sandbox Reserved 1716: Difference between revisions
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== Inhibition of VKOR == | |||
== | |||
[https://en.wikipedia.org/wiki/Warfarin Warfarin] is the most common [https://en.wikipedia.org/wiki/Vitamin_K_antagonist Vitamin K antagonist (VKA)]. Warfarin is a competitive inhibitor, taking the place of Vitamin K Epoxide (VKO) in the active site of Vitamin K Epoxide Reductase (VKOR). When warfarin binds in the active site, it causes VKOR to go into the closed conformation. | [https://en.wikipedia.org/wiki/Warfarin Warfarin] is the most common [https://en.wikipedia.org/wiki/Vitamin_K_antagonist Vitamin K antagonist (VKA)]. Warfarin is a competitive inhibitor, taking the place of Vitamin K Epoxide (VKO) in the active site of Vitamin K Epoxide Reductase (VKOR). When warfarin binds in the active site, it causes VKOR to go into the closed conformation. | ||
[[Image:warfarin.jpg|400 px|right|thumb|Figure 7. 2-Dimensional structure of Warfarin]] | [[Image:warfarin.jpg|400 px|right|thumb|Figure 7. 2-Dimensional structure of Warfarin]] | ||
=== Binding === | === Binding === | ||
Warfarin also forms hydrogen bonds with <scene name='90/904322/Tyr_asn_binding_warfarin/2'>Asn80 and Tyr139</scene>. The specific bonds are between Asn80 and the 2-ketone group of warfarin and Tyr139 with the 4-hydroxyl group of warfarin. The rest of the warfarin interaction is determined by hydrophobic interactions. These hydrogen bonds provide the necessary recognition for the ligand to bind to the binding site to VKOR. | Warfarin also forms hydrogen bonds with <scene name='90/904322/Tyr_asn_binding_warfarin/2'>Asn80 and Tyr139</scene>. The specific bonds are between Asn80 and the 2-ketone group of warfarin and Tyr139 with the 4-hydroxyl group of warfarin. The rest of the warfarin interaction is determined by hydrophobic interactions. These hydrogen bonds provide the necessary recognition for the ligand to bind to the binding site to VKOR. | ||
Warfarin binds with a slight difference compared to VKO. Warfarin binds at a slightly different angle. This creates a difference in how the cap loop and anchor domain interact and that affects the placement of | Warfarin binds with a slight difference compared to VKO. Warfarin binds at a slightly different angle. This creates a difference in how the cap loop and anchor domain interact and that affects the placement of <scene name='90/904322/Arg58/3'>Arg58</scene>. With VKO, Arg58 from the cap loop directly interacts with <scene name='90/904322/Arg58_vko/3'>Glu67</scene>. However, when warfarin binds, Arg58 is inserted between <scene name='90/904322/Arg58_warfarin/1'>Glu67 and His68</scene> of the anchor domain. | ||
=== Disease === | === Disease === | ||
Vitamin K antagonists are first line therapeutics in the treatment of thromboembolic diseases, like a stroke or heart attack. Warfarin is the most common medication for this treatment, acting as a blood thinner. Warfarin binding to VKOR prevents the triggering of coagulation factors that form blood clots. | |||
== References == | == References == | ||
<ref name="Goodstadt">PMID:15276181</ref> Goodstadt, L., & Ponting, C. P. (2004). Vitamin K epoxide reductase: homology, active site and catalytic mechanism. ''Trends in biochemical sciences, 29''(6), 289–292. https://doi.org/10.1016/j.tibs.2004.04.004 | <ref name="Goodstadt">PMID:15276181</ref> Goodstadt, L., & Ponting, C. P. (2004). Vitamin K epoxide reductase: homology, active site and catalytic mechanism. ''Trends in biochemical sciences, 29''(6), 289–292. https://doi.org/10.1016/j.tibs.2004.04.004 | ||
