Sandbox Reserved 957: Difference between revisions

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OCA, Michael Pierrelee

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 Image:Sildenafilspace.jpg|500px|Sildenafil Inhibitor in the space in the enzyme</gallery>
-* PDE5 inhibitors might help physical condition in Duchene muscular dystrophy<ref>[14]</ref>, improve of cognitive function <ref>[9]</ref>and have antidepressant effect<ref>[10]</ref> , also they might have an artero<ref>[15]</ref> and endothelial cell protective effect<ref>[16]</ref> so they have cardiac protection effect<ref>[17]</ref> (controversial, cf. clinical trial “RELAX”), finally they slow tumer cell growth (Tadalafil-like)[18]<br \>
+* PDE5 inhibitors might help physical condition in Duchene muscular dystrophy<ref>[14]</ref>, improve of cognitive function <ref>[9]</ref>and have antidepressant effect<ref>[10]</ref> , also they might have an artero<ref>[15]</ref> and endothelial cell protective effect<ref>[16]</ref> so they have cardiac protection effect<ref>[17]</ref> (controversial, cf. clinical trial “RELAX”), finally they slow tumer cell growth (Tadalafil-like)<ref>[18]</ref><br \>
 * There are other PDE5 inhibitors: IBMX, Icarisid II and Udenafil.<br \>
 * No interaction between the M site and the inhibitors<br \>
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 Binding amino acid for the Sildenafil:<br \>
-* R1 group have contacts with <scene name='60/604476/R1-1/1'>Gln817</scene> (2 hydrogen bounds, so it increases Sildenafil affinity), <scene name='60/604476/R1-1/1'>Phe820</scene> (Sildenafil stacks against it), <scene name='60/604476/R1-1/1'>Try612</scene> (hydrogen bound so it increases Sildenafil affinity [24]), <scene name='60/604476/R1-1/1'>Leu765</scene> and <scene name='60/604476/R1-1/1'>Ala767</scene> [21]. And there is hydrophobic interactions between the pyrazol ring and residues <scene name='60/604476/R1-2/1'>Val782, Leu785, Tyr612 and Phe820</scene> [24].<br \>
+* R1 group have contacts with <scene name='60/604476/R1-1/1'>Gln817</scene> (2 hydrogen bounds, so it increases Sildenafil affinity), <scene name='60/604476/R1-1/1'>Phe820</scene> (Sildenafil stacks against it), <scene name='60/604476/R1-1/1'>Try612</scene> (hydrogen bound so it increases Sildenafil affinity <ref>[24]</ref>), <scene name='60/604476/R1-1/1'>Leu765</scene> and <scene name='60/604476/R1-1/1'>Ala767</scene> <ref>[21]</ref>. And there is hydrophobic interactions between the pyrazol ring and residues <scene name='60/604476/R1-2/1'>Val782, Leu785, Tyr612 and Phe820</scene> <ref>[24]</ref>.<br \>
 * R2 group is in the H pocket and has Van der Waals bounds with Val 782, Ala 783, Phe 786, Leu 804, Ile 813, Gln 817, Phe801. And interaction Pi-Pi between the phenyl ring and the Phe820.<br \>
 * R3 group is in the L pocket and has contacts with <scene name='60/604476/662_804/1'>Asn 662, Ser 663, Tyr 664, Ile 665 (in the H-loop), Leu 804, Phe 801</scene>
-* <scene name='60/604476/Gly659/2'>Gly659</scene> is modified by Sildenafil presence in PDE5, ϕ and φ angles are increased (from 76-105° to 104-109° for ϕ and from 3-22° to 139-141° for φ) and ω angle is not changed. [21]<br \>
+* <scene name='60/604476/Gly659/2'>Gly659</scene> is modified by Sildenafil presence in PDE5, ϕ and φ angles are increased (from 76-105° to 104-109° for ϕ and from 3-22° to 139-141° for φ) and ω angle is not changed. <ref>[21]</ref><br \>
 H-loop:<br \>
 For each inhibitor, <scene name='60/604476/H_loop/1'>H-loop</scene> take a different and originally (comparatively to other PDEs) tertiary structure (and there are also minor modifications of <scene name='60/604476/N_loop/1'>the N-loop (788-811)</scene> ):<br \>
-* For an unliganded PDE5, <scene name='60/604476/H_loop/1'>H-loop</scene>  take a coil conformation. [21]<br \>
+* For an unliganded PDE5, <scene name='60/604476/H_loop/1'>H-loop</scene>  take a coil conformation. <ref>[21]</ref><br \>
-* In case of Sildenafil binding, a turn and an 3ind10<scene name='60/604476/3-10helix/1'> helix (from 672 to 675)</scene> appear, and  <scene name='60/604476/668_676/1'>from 668 to 676</scene> The all loop cover the active site (by migrate of 24 Å from unliganded PDE5 loop structure, so the active site become a closed pocket). [21]<br \>
+* In case of Sildenafil binding, a turn and an 3ind10<scene name='60/604476/3-10helix/1'> helix (from 672 to 675)</scene> appear, and  <scene name='60/604476/668_676/1'>from 668 to 676</scene> The all loop cover the active site (by migrate of 24 Å from unliganded PDE5 loop structure, so the active site become a closed pocket). <ref>[21]</ref><br \>
 * H-loop is less important in the interactions for Sildenafil and Icarisid II than cGMP.<br \>
 == Regulation ==
-As it is written over, there are 2 regulatory domains (GAF A and GAF B). In cGMP pathway, PDE5 allows a negative feedback of the molecule: first, in presence of cGMP, it binds GAF A which stimulates the catalysis in the active site, and vice versa. Moreover, cGMP actives PKG which phophorylates PDE5, that is stimulated by the presence of cGMP on the GAF A or/and the active site. If the protein is not binding with cGMP but it is phophorylated, that stimulates the binding of cGMP on GAF A and the catalytic site. So cGMP presence overstimulates the catalysis [19]. And it also increase inhibitor's affinity[20] and without cGMP, inhibitor don’t bind the PDE5 [22].<br \>
+As it is written over, there are 2 regulatory domains (GAF A and GAF B). In cGMP pathway, PDE5 allows a negative feedback of the molecule: first, in presence of cGMP, it binds GAF A which stimulates the catalysis in the active site, and vice versa. Moreover, cGMP actives PKG which phophorylates PDE5, that is stimulated by the presence of cGMP on the GAF A or/and the active site. If the protein is not binding with cGMP but it is phophorylated, that stimulates the binding of cGMP on GAF A and the catalytic site. So cGMP presence overstimulates the catalysis <ref>[19]</ref>. And it also increase inhibitor's affinity<ref>[20]</ref> and without cGMP, inhibitor don’t bind the PDE5 <ref>[22]</ref>.<br \>
 == The NO Pathway ==
-In the penile erection example, the nervous cell and/or epithelial cells are produced Nitrogen Oxide (NO) by the NOS (NO synthetase) from L-arginine and O2. They release NO in the extracellular environment going into vascular smooth cells and binding the Guanylyl Cyclase. This enzyme synthesizes cGMP from GMP, which stimulates the PKG. Finally, the calcium level is lower and the muscle cell relaxes and the Corpus Cavernosum rigidity increases. The PDE5 regulates the cGMP level making a negative feedback and can stop the rigidity. [22]<br \>
+In the penile erection example, the nervous cell and/or epithelial cells are produced Nitrogen Oxide (NO) by the NOS (NO synthetase) from L-arginine and O2. They release NO in the extracellular environment going into vascular smooth cells and binding the Guanylyl Cyclase. This enzyme synthesizes cGMP from GMP, which stimulates the PKG. Finally, the calcium level is lower and the muscle cell relaxes and the Corpus Cavernosum rigidity increases. The PDE5 regulates the cGMP level making a negative feedback and can stop the rigidity. <ref>[22]</ref><br \>
 </StructureSection>
 == References ==
 <references/>