Sandbox Reserved 1709: Difference between revisions

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=== Active Site ===

Within the four transmembrane helices lies the <scene name='90/906893/Binding_pocket/1'>binding pocket</scene>. The binding pocket ~~is comprised of a~~ <scene name='90/906893/~~Hydrophobic~~/2'>~~hydrophobic region~~</scene> ~~containing~~ <scene name='90/906893/~~Active_site~~/7'>~~two hydrophilic residues~~</scene>~~, N80 and Y139,~~ that ~~interact with the substrate. The hydrophobic pocket~~ provides specificity to the region ~~while the~~ hydrophilic residues hydrogen bond to the substrate, providing recognition and increasing specificity. The <scene name='90/906893/Disulfide_-_132/1'>C132-C135 disulfide bridge</scene> above the binding pocket provides stabilization when a substrate is bound. This bridge provides increased stability for the binding site as it interacts with and binds substrates or inhibitors ~~of VKOR~~. The hydrophilic residues provide <scene name='90/~~904314~~/K_hbonds/1'>hydrogen bonds</scene> when interacting with substrates for specificity and recognition. Upon binding, VKOR will transition into the closed conformation allowing the catalytic mechanism to commence.

Within the four transmembrane helices lies the <scene name='90/906893/Binding_pocket/1'>binding pocket</scene>. The binding pocket holds two <scene name='90/906893/Active_site/7'>two hydrophilic residues</scene> active site residues, N80 and Y139, that interact with the substrate. N80 and Y139 are surrounded by a <scene name='90/906893/Hydrophobic/2'>hydrophobic region</scene> that provides specificity to the region. The hydrophilic residues hydrogen bond to the substrate, providing recognition and increasing specificity. The <scene name='90/906893/Disulfide_-_132/1'>C132-C135 disulfide bridge</scene> above the binding pocket provides stabilization when a substrate is bound. This bridge provides increased stability for the binding site as it interacts with and binds substrates or inhibitors. The hydrophilic residues provide <scene name='90/906893/K_hbonds/1'>hydrogen bonds</scene> when interacting with substrates for specificity and recognition. Upon binding, VKOR will transition into the closed conformation allowing the catalytic mechanism to commence.

==Catalytic Mechanism of VKOR==

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=== Afflictions ===

Since activated Vitamin K plays a crucial role in blood coagulation, defects in the function and enzymatic activity of VKOR may detrimentally effect Vitamin K's ability to promote blood clotting. Mutations in VKOR also increase susceptibility to [https://en.wikipedia.org/wiki/Vascular_disease Vascular Disease], such as a [https://en.wikipedia.org/wiki/Stroke Stroke] <ref>DOI 10.1161/CIRCULATIONAHA.105.580167</ref>. Vitamin K is also important in maintaining bone health, with inactivity of VKOR linked to decreased bone density and [https://en.wikipedia.org/wiki/Osteoporosis Osteoporosis]<ref>DOI 10.7759/cureus.10816</ref>.

=== Inhibition ===

[[Image:Warfarin.png |400 px| right| thumb | Figure 4. Structure of Warfarin.]]

The most common way to treat blood clotting is using the VKOR inhibitor, <scene name='90/904314/Vkor_with_warfarin_bound/1'>warfarin</scene>. [https://en.wikipedia.org/wiki/Warfarin Warfarin] outcompetes KO<ref>PMID: 29261922</ref>, such that Vitamin K cannot be activated to promote coagulation in the blood. Warfarin will enter the binding pocket of VKOR, creating strong <scene name='90/~~904314~~/Vkor_with_warfarin_bound/5'>hydrogen bonds</scene> with the active site residues, N80 and Y139. Mutations of VKOR can lead to warfarin resistance which decreases its anticoagulation effects. Different mutations introduce varying degrees of resistance. These mutations are important to recognize as [https://en.wikipedia.org/wiki/Superwarfarin super-warfarin's] can be overly effective in anticoagulation to ~~the point of fatality~~.

The most common way to treat blood clotting is using the VKOR inhibitor, <scene name='90/904314/Vkor_with_warfarin_bound/1'>warfarin</scene>. [https://en.wikipedia.org/wiki/Warfarin Warfarin] outcompetes KO<ref>PMID: 29261922</ref>, such that Vitamin K cannot be activated to promote coagulation in the blood. Warfarin will enter the binding pocket of VKOR, creating strong <scene name='90/906893/Vkor_with_warfarin_bound/3'>hydrogen bonds</scene> with the active site residues, N80 and Y139. Mutations of VKOR can lead to warfarin resistance which decreases its anticoagulation effects. Different mutations introduce varying degrees of resistance. These mutations are important to recognize as [https://en.wikipedia.org/wiki/Superwarfarin super-warfarin's] can be overly effective in anticoagulation and become detrimental to blood flow.

=== Mutations ===

~~Within the <scene name='90/904314/Active_site/2'>binding pocket</scene> mutations~~ of the <scene name='90/~~904314~~/Vkor_with_warfarin_bound/4'>active site residues</scene> can occur. These mutations can be detrimental to the VKOR structure and function<ref>DOI 10.1126/science.abc5667</ref>. Two of the most common mutations occur to residues N80 and Y139 ~~when they are mutated~~ to <scene name='90/~~904314~~/Active_site_mutations/2'>A80 and F139</scene>. The change in polarity of these mutations from polar to nonpolar will cause a decrease in recognition and stabilization due to the inability to provide hydrogen bonds ~~to the bound substrate~~.

Mutations of the <scene name='90/906893/Vkor_with_warfarin_bound/4'>active site residues</scene> can occur within the binding pocket of VKOR. These mutations can be detrimental to the VKOR structure and function<ref>DOI 10.1126/science.abc5667</ref>. Two of the most common mutations occur to residues N80 and Y139 mutating them to <scene name='90/906893/Active_site_mutations/3'>A80 and F139</scene>. The change in polarity of these mutations from polar to nonpolar will cause a decrease in recognition and stabilization due to the inability to provide hydrogen bonds. <scene name='90/906893/Hydrophobic/3'>hydrophobic residues</scene>

Sandbox Reserved 1709: Difference between revisions

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@@ Line 20: / Line 20: @@
 === Active Site ===
-Within the four transmembrane helices lies the <scene name='90/906893/Binding_pocket/1'>binding pocket</scene>. The binding pocket is comprised of a <scene name='90/906893/Hydrophobic/2'>hydrophobic region</scene> containing <scene name='90/906893/Active_site/7'>two hydrophilic residues</scene>, N80 and Y139, that interact with the substrate. The hydrophobic pocket provides specificity to the region while the hydrophilic residues hydrogen bond to the substrate, providing recognition and increasing specificity. The <scene name='90/906893/Disulfide_-_132/1'>C132-C135 disulfide bridge</scene> above the binding pocket provides stabilization when a substrate is bound. This bridge provides increased stability for the binding site as it interacts with and binds substrates or inhibitors of VKOR. The hydrophilic residues provide <scene name='90/904314/K_hbonds/1'>hydrogen bonds</scene> when interacting with substrates for specificity and recognition. Upon binding, VKOR will transition into the closed conformation allowing the catalytic mechanism to commence.
+Within the four transmembrane helices lies the <scene name='90/906893/Binding_pocket/1'>binding pocket</scene>. The binding pocket holds two <scene name='90/906893/Active_site/7'>two hydrophilic residues</scene> active site residues, N80 and Y139, that interact with the substrate. N80 and Y139 are surrounded by a <scene name='90/906893/Hydrophobic/2'>hydrophobic region</scene> that provides specificity to the region. The hydrophilic residues hydrogen bond to the substrate, providing recognition and increasing specificity. The <scene name='90/906893/Disulfide_-_132/1'>C132-C135 disulfide bridge</scene> above the binding pocket provides stabilization when a substrate is bound. This bridge provides increased stability for the binding site as it interacts with and binds substrates or inhibitors. The hydrophilic residues provide <scene name='90/906893/K_hbonds/1'>hydrogen bonds</scene> when interacting with substrates for specificity and recognition. Upon binding, VKOR will transition into the closed conformation allowing the catalytic mechanism to commence.
 ==Catalytic Mechanism of VKOR==
@@ Line 34: / Line 34: @@
 === Afflictions ===
 Since activated Vitamin K plays a crucial role in blood coagulation, defects in the function and enzymatic activity of VKOR may detrimentally effect Vitamin K's ability to promote blood clotting. Mutations in VKOR also increase susceptibility to [https://en.wikipedia.org/wiki/Vascular_disease Vascular Disease], such as a [https://en.wikipedia.org/wiki/Stroke Stroke] <ref>DOI 10.1161/CIRCULATIONAHA.105.580167</ref>. Vitamin K is also important in maintaining bone health, with inactivity of VKOR linked to decreased bone density and [https://en.wikipedia.org/wiki/Osteoporosis Osteoporosis]<ref>DOI 10.7759/cureus.10816</ref>.
 === Inhibition ===
 [[Image:Warfarin.png |400 px| right| thumb | Figure 4. Structure of Warfarin.]]
-The most common way to treat blood clotting is using the VKOR inhibitor, <scene name='90/904314/Vkor_with_warfarin_bound/1'>warfarin</scene>. [https://en.wikipedia.org/wiki/Warfarin Warfarin] outcompetes KO<ref>PMID: 29261922</ref>, such that Vitamin K cannot be activated to promote coagulation in the blood. Warfarin will enter the binding pocket of VKOR, creating strong <scene name='90/904314/Vkor_with_warfarin_bound/5'>hydrogen bonds</scene> with the active site residues, N80 and Y139. Mutations of VKOR can lead to warfarin resistance which decreases its anticoagulation effects. Different mutations introduce varying degrees of resistance. These mutations are important to recognize as [https://en.wikipedia.org/wiki/Superwarfarin super-warfarin's] can be overly effective in anticoagulation to the point of fatality.
+The most common way to treat blood clotting is using the VKOR inhibitor, <scene name='90/904314/Vkor_with_warfarin_bound/1'>warfarin</scene>. [https://en.wikipedia.org/wiki/Warfarin Warfarin] outcompetes KO<ref>PMID: 29261922</ref>, such that Vitamin K cannot be activated to promote coagulation in the blood. Warfarin will enter the binding pocket of VKOR, creating strong <scene name='90/906893/Vkor_with_warfarin_bound/3'>hydrogen bonds</scene> with the active site residues, N80 and Y139. Mutations of VKOR can lead to warfarin resistance which decreases its anticoagulation effects. Different mutations introduce varying degrees of resistance. These mutations are important to recognize as [https://en.wikipedia.org/wiki/Superwarfarin super-warfarin's] can be overly effective in anticoagulation and become detrimental to blood flow.
 === Mutations ===
-Within the <scene name='90/904314/Active_site/2'>binding pocket</scene> mutations of the <scene name='90/904314/Vkor_with_warfarin_bound/4'>active site residues</scene> can occur. These mutations can be detrimental to the VKOR structure and function<ref>DOI 10.1126/science.abc5667</ref>. Two of the most common mutations occur to residues N80 and Y139 when they are mutated to <scene name='90/904314/Active_site_mutations/2'>A80 and F139</scene>. The change in polarity of these mutations from polar to nonpolar will cause a decrease in recognition and stabilization due to the inability to provide hydrogen bonds to the bound substrate.
+Mutations of the <scene name='90/906893/Vkor_with_warfarin_bound/4'>active site residues</scene> can occur within the binding pocket of VKOR. These mutations can be detrimental to the VKOR structure and function<ref>DOI 10.1126/science.abc5667</ref>. Two of the most common mutations occur to residues N80 and Y139 mutating them to <scene name='90/906893/Active_site_mutations/3'>A80 and F139</scene>. The change in polarity of these mutations from polar to nonpolar will cause a decrease in recognition and stabilization due to the inability to provide hydrogen bonds. <scene name='90/906893/Hydrophobic/3'>hydrophobic residues</scene>