Sandbox Reserved 1717: Difference between revisions

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=== Binding ===

In its resting state, VKOR is in its <scene name='90/904322/Open_conformation/2'>open conformation</scene>. The Vitamin K epoxide enters through the <scene name='90/904322/Tunnel/7'>isoprenyl-chain tunnel</scene>. The tunnel is located between <scene name='90/904322/Tunnel/8'>TM2 and TM3</scene>. The carbonyls on the VK epoxide bind to <scene name='90/904322/Vko_binding/1'>Asn80 and Tyr139</scene> on VKOR. With Vitamin K epoxide bound, the ~~cysteines of VKOR are partially oxidized, and concurrently reduce the substrate. A disulfide bond then forms between Cys51 and Cys132, resulting in the closed~~ conformation. This leaves the sulfur on Cys43 and the sulfur on Cys135 protonated. The available hydrogens on these cysteines are utilized in reducing the epoxide. First, the free sulfur on Cys43 attacks Cys51 to form a new disulfide bond. With the loss of hydrogen from ~~Cys43 in the formation of the new disulfide bond, an electron transfer is made~~ to ~~VKO. Next~~, the sulfur on Cys132 and the sulfur on Cys135 form a new disulfide bond. The hydrogen that was present on Cys135 is lost in the formation of the disulfide bond, allowing for an electron transfer to the oxygen of the epoxide. With these cysteine pairs formed, VKOR is left in an open conformation. The end products are Vitamin K/quinone and water.

In its resting state, VKOR is in its <scene name='90/904322/Open_conformation/2'>open conformation</scene>. The Vitamin K epoxide enters through the <scene name='90/904322/Tunnel/7'>isoprenyl-chain tunnel</scene>. The tunnel is located between <scene name='90/904322/Tunnel/8'>TM2 and TM3</scene>.<ref name="Li">PMID:20110994</ref> The carbonyls on the VK epoxide bind to <scene name='90/904322/Vko_binding/2'>Asn80 and Tyr139</scene> on VKOR. With Vitamin K epoxide bound, the conformation transitions from open to closed, where the catalytic process will begin.

== Warfarin ==

[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 6. Warfarin structure]]

[[Image:warfarin.jpg|400 px|left|thumb|Figure 6. Warfarin structure]]

=== Binding ===

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Warfarin still forms Hydrogen bonds with <scene name='90/904322/Asn80_tyr139_warfarin/1'>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 pocket is hydrophobic interactions. The H bonds are necessary for the recognition of the ligand in the binding site of VKOR.

There is a slight difference in the way in which warfarin binds compared to VKO. Warfarin binds are a slightly different angle. This creates a difference in how the cap loop and anchor domain interact, and that noticeable difference is with <scene name='90/904322/Arg58/4'>Arg58</scene>. With VKO, Arg58, located in the cap loop, directly interacts with <scene name='90/904322/Arg58_vko/5'>Glu67</scene> when VKO is bound. When warfarin binds, Arg58 is found inserted between<scene name='90/904322/Arg58_warfarin/2'>Glu67 and His68</scene> of the anchor domain.

There is a slight difference in the way in which warfarin binds compared to VKO. Warfarin binds are a slightly different angle (Fig.7). This creates a difference in how the cap loop and anchor domain interact, and that noticeable difference is with <scene name='90/904322/Arg58/4'>Arg58</scene>. With VKO, Arg58, located in the cap loop, directly interacts with <scene name='90/904322/Arg58_vko/5'>Glu67</scene> when VKO is bound. When warfarin binds, Arg58 is found inserted between <scene name='90/904322/Arg58_warfarin/2'>Glu67 and His68</scene> of the anchor domain.<ref name=”Liu”>PMID:33154105</ref>

[[Image:VKO and Warfarin binding.jpg|600 px|right|thumb|Figure 6. The slight angle change in which VKO(left) and warfarin(right) bind. The location of the cap domain and how it differs between each is apparent.]]

=== Disease ===

[https://en.wikipedia.org/wiki/Vitamin_K_antagonist#:~:text=Vitamin%20K%20antagonists%20(VKA)%20are,the%20recycling%20of%20vitamin%20K. Vitamin K Antagonists] play a big role in the treatment of thromboembolic diseases, like a stroke or heart attack.<ref name="Goy">PMID:23034830</ref> [https://en.wikipedia.org/wiki/Warfarin Warfarin] is the most common medication for this treatment, acting as a blood thinner. Warfarin binding in VKOR overall prevents the triggering of coagulation factors that form blood clots.

==References==

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@@ Line 55: / Line 55: @@
 === Binding ===
-In its resting state, VKOR is in its <scene name='90/904322/Open_conformation/2'>open conformation</scene>. The Vitamin K epoxide enters through the <scene name='90/904322/Tunnel/7'>isoprenyl-chain tunnel</scene>. The tunnel is located between <scene name='90/904322/Tunnel/8'>TM2 and TM3</scene>. The carbonyls on the VK epoxide bind to <scene name='90/904322/Vko_binding/1'>Asn80 and Tyr139</scene> on VKOR. With Vitamin K epoxide bound, the cysteines of VKOR are partially oxidized, and concurrently reduce the substrate. A disulfide bond then forms between Cys51 and Cys132, resulting in the closed conformation. This leaves the sulfur on Cys43 and the sulfur on Cys135 protonated. The available hydrogens on these cysteines are utilized in reducing the epoxide. First, the free sulfur on Cys43 attacks Cys51 to form a new disulfide bond. With the loss of hydrogen from Cys43 in the formation of the new disulfide bond, an electron transfer is made to VKO. Next, the sulfur on Cys132 and the sulfur on Cys135 form a new disulfide bond. The hydrogen that was present on Cys135 is lost in the formation of the disulfide bond, allowing for an electron transfer to the oxygen of the epoxide. With these cysteine pairs formed, VKOR is left in an open conformation. The end products are Vitamin K/quinone and water.
+In its resting state, VKOR is in its <scene name='90/904322/Open_conformation/2'>open conformation</scene>. The Vitamin K epoxide enters through the <scene name='90/904322/Tunnel/7'>isoprenyl-chain tunnel</scene>. The tunnel is located between <scene name='90/904322/Tunnel/8'>TM2 and TM3</scene>.<ref name="Li">PMID:20110994</ref> The carbonyls on the VK epoxide bind to <scene name='90/904322/Vko_binding/2'>Asn80 and Tyr139</scene> on VKOR. With Vitamin K epoxide bound, the conformation transitions from open to closed, where the catalytic process will begin.
 == Warfarin ==
 [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 6. Warfarin structure]]
+[[Image:warfarin.jpg|400 px|left|thumb|Figure 6. Warfarin structure]]
 === Binding ===
@@ Line 66: / Line 66: @@
 Warfarin still forms Hydrogen bonds with <scene name='90/904322/Asn80_tyr139_warfarin/1'>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 pocket is hydrophobic interactions. The H bonds are necessary for the recognition of the ligand in the binding site of VKOR.
-There is a slight difference in the way in which warfarin binds compared to VKO. Warfarin binds are a slightly different angle. This creates a difference in how the cap loop and anchor domain interact, and that noticeable difference is with <scene name='90/904322/Arg58/4'>Arg58</scene>. With VKO, Arg58, located in the cap loop, directly interacts with <scene name='90/904322/Arg58_vko/5'>Glu67</scene> when VKO is bound. When warfarin binds, Arg58 is found inserted between<scene name='90/904322/Arg58_warfarin/2'>Glu67 and His68</scene> of the anchor domain.
+There is a slight difference in the way in which warfarin binds compared to VKO. Warfarin binds are a slightly different angle (Fig.7). This creates a difference in how the cap loop and anchor domain interact, and that noticeable difference is with <scene name='90/904322/Arg58/4'>Arg58</scene>. With VKO, Arg58, located in the cap loop, directly interacts with <scene name='90/904322/Arg58_vko/5'>Glu67</scene> when VKO is bound. When warfarin binds, Arg58 is found inserted between <scene name='90/904322/Arg58_warfarin/2'>Glu67 and His68</scene> of the anchor domain.<ref name=”Liu”>PMID:33154105</ref>
+[[Image:VKO and Warfarin binding.jpg|600 px|right|thumb|Figure 6. The slight angle change in which VKO(left) and warfarin(right) bind. The location of the cap domain and how it differs between each is apparent.]]
 === Disease ===
 [https://en.wikipedia.org/wiki/Vitamin_K_antagonist#:~:text=Vitamin%20K%20antagonists%20(VKA)%20are,the%20recycling%20of%20vitamin%20K. Vitamin K Antagonists] play a big role in the treatment of thromboembolic diseases, like a stroke or heart attack.<ref name="Goy">PMID:23034830</ref> [https://en.wikipedia.org/wiki/Warfarin Warfarin] is the most common medication for this treatment, acting as a blood thinner. Warfarin binding in VKOR overall prevents the triggering of coagulation factors that form blood clots.
 ==References==
 <references/>