Sandbox Reserved 957: Difference between revisions

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<Structure load='2H40' size='350' frame='true' align='right' caption='Insert caption here' scene='Insert optional scene name here' />{{Sandbox_ESBS}}

==Introduction==

PDE5, phosphodiesterase 5 (EC 3.1.4.35), is an abundant protein in cell of airway and visceral smooth muscle and vascular cell. It can be found in epithelial cell and in Purkinje cell of the cerebella <ref>[1]</ref> and platelets and Corpus Cavernosum. In particular, it is implied in the NO pathway of penile erection and so in the Erectile Dysfunction (ED) [22].

PDE5, phosphodiesterase 5 (EC 3.1.4.35), is an abundant protein in cell of airway and visceral smooth muscle and vascular cell. It can be found in epithelial cell and in Purkinje cell of the cerebella <ref>[1]</ref> and platelets and Corpus Cavernosum. In particular, it is implied in the NO pathway of penile erection and so in the Erectile Dysfunction (ED) <ref>[22]</ref>.

There are 11 families of PDE (from 1 to 9), there is 21 genes for PDE which code 60 different PDE. For the PDE5A, the only PDE5 subcategory, there are 4 isoforms but their catalytic domain is the same [24].

There are 11 families of PDE (from 1 to 9), there is 21 genes for PDE which code 60 different PDE. For the PDE5A, the only PDE5 subcategory, there are 4 isoforms but their catalytic domain is the same <ref>[24]</ref>.

The catalytic reaction is the hydrolysis of guanosine cyclic monophosphate into linear guanosine monophosphate. This cGMP-specific enzyme have 3 domains (from N terminal to C terminal) : GAF A, GAF B and a conserved catalytic domain regard to other PDEs of the family. Only cGMP can bind GAF A or GAF B and it stimulates the hydrolysis.

We study here the PDE5A catalytic fragment formed of amino acid residues from the 535th to the 860th [23]. In the inhibition, we talk about the Sildenafil mostly, because it's the most known (active ingredient in the Viagra®).

We study here the PDE5A catalytic fragment formed of amino acid residues from the 535th to the 860th <ref>[23]</ref>. In the inhibition, we talk about the Sildenafil mostly, because it's the most known (active ingredient in the Viagra®).

Problem in the PBD files: N-loop (from the 788th to the 881th residues) is not complete.

== Structure of catalytic site ==

The only catalytic fragment is effective, so the regulations sites and the dimerization to a trimeric enzyme are useless for the catalytic activity. Moreover, this catalytic moiety has the same activity that the wild-type enzyme, so maybe the enzyme is monomeric in the cell [24].

The only catalytic fragment is effective, so the regulations sites and the dimerization to a trimeric enzyme are useless for the catalytic activity. Moreover, this catalytic moiety has the same activity that the wild-type enzyme, so maybe the enzyme is monomeric in the cell <ref>[24]</ref>.

Catalytic domain is conserved for the PDE family, between 20% and 40%, and the variant reactions of the PDE inhibitors on the different PDEs may be caused by the more variant regulatory sites [25].

Catalytic domain is conserved for the PDE family, between 20% and 40%, and the variant reactions of the PDE inhibitors on the different PDEs may be caused by the more variant regulatory sites <ref>[25]</ref>.

The catalytic domain has 3 helical subdomains [24]:

The catalytic domain has 3 helical subdomains <ref>[24]</ref>:

* A N-terminal cyclin-fold region with eight helixes [26]: 5 α-helixes (1, 3, 5, 6 and 8) and 3 3ind10-helixes (2,4, and 7),<scene name='60/604476/537_678/3'> from the 537th to the 678th residues</scene>.

* A N-terminal cyclin-fold region with eight helixes <ref>[26]</ref>: 5 α-helixes (1, 3, 5, 6 and 8) and 3 3ind10-helixes (2,4, and 7),<scene name='60/604476/537_678/3'> from the 537th to the 678th residues</scene>.

* A linker domain: two antiparallels α9 and α10 helixes, and between a disordered region,<scene name='60/604476/679-725/2'>from the 679th to the 725th residues</scene>.

* A C-terminal buddle pocket with eight helixes: 5 long α-helixes (11, 12, 14, 17 and 18) and 3 smaller helixes (13, 15 and 16),<scene name='60/604476/726-860/2'> from the 726th to the 860th residues</scene>.

** α5, 6 and 8 surround α3 and form an interface with the linker domain and the CTD.

The catalytic site is a pocket which is 330Å in volume and a deep of 10Å, with a narrow entry. There are 4 regions: M (with 2 metallic ions), H (hydrophobic), Q (for the substrate), L (the lid or “H-Loop” on both N-term and linker domain). M site is surrounded by the helixes α6, 8, 9, 10 and 12. A majority of aliphatic or hydrophobic residues, that creates the hydrophobic pocket [2].

The catalytic site is a pocket which is 330Å in volume and a deep of 10Å, with a narrow entry. There are 4 regions: M (with 2 metallic ions), H (hydrophobic), Q (for the substrate), L (the lid or “H-Loop” on both N-term and linker domain). M site is surrounded by the helixes α6, 8, 9, 10 and 12. A majority of aliphatic or hydrophobic residues, that creates the hydrophobic pocket <ref>[2]</ref>.

M site contains:

* The Me-1 and Me-2 sites are occupied by metal ions, Zinc within Me-1 and within Me-2, Zinc, Magnesium or Manganese [5],

* The Me-1 and Me-2 sites are occupied by metal ions, Zinc within Me-1 and within Me-2, Zinc, Magnesium or Manganese <ref>[5]</ref>,

* The residues <scene name='60/604476/His617_asp654_asp764_his653/1'>His617, Asp654, Asp764, His653</scene> and two H2O (W1 et W2) binding zinc:

** The crucial <scene name='60/604476/Asp764/1'>Asp764</scene> [3] and the conserved His617 and 653[4], which bind one Zinc ion, are fundamental for the catalytic activity.

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== Inhibition ==

In the treatment erection dysfunction, the inhibitors Sildenafil, Vardenafil and Tadalafil are used, like in the pulmonary hypertension[6]. Sildenafil may cure sleeping trouble after a intercontinental travel [11], may help to recover neural liaisons after an injury (the motor function[12] and the sensory motor function[13]) and can be vascular effects. ~~[[Image:Sildenafil.jpg]]~~

In the treatment erection dysfunction, the inhibitors Sildenafil, Vardenafil and Tadalafil are used, like in the pulmonary hypertension[6]. Sildenafil may cure sleeping trouble after a intercontinental travel [11], may help to recover neural liaisons after an injury (the motor function[12] and the sensory motor function[13]) and can be vascular effects.

* PDE5 inhibitors might help physical condition in Duchene muscular dystrophy[14], improve of cognitive function [9]and have antidepressant effect[10] , also they might have an artero[15] and endothelial cell protective effect[16] so they have cardiac protection effect[17] (controversial, cf. clinical trial “RELAX”), finally they slow tumer cell growth (Tadalafil-like)[18]

@@ Line 1: / Line 1: @@
 <Structure load='2H40' size='350' frame='true' align='right' caption='Insert caption here' scene='Insert optional scene name here' />{{Sandbox_ESBS}}<!-- PLEASE ADD YOUR CONTENT BELOW HERE -->
 ==Introduction==
-PDE5, phosphodiesterase 5 (EC 3.1.4.35), is an abundant protein in cell of airway and visceral smooth muscle and vascular cell. It can be found in epithelial cell and in Purkinje cell of the cerebella <ref>[1]</ref> and platelets and Corpus Cavernosum. In particular, it is implied in the NO pathway of penile erection and so in the Erectile Dysfunction (ED) [22].<br \>
+PDE5, phosphodiesterase 5 (EC 3.1.4.35), is an abundant protein in cell of airway and visceral smooth muscle and vascular cell. It can be found in epithelial cell and in Purkinje cell of the cerebella <ref>[1]</ref> and platelets and Corpus Cavernosum. In particular, it is implied in the NO pathway of penile erection and so in the Erectile Dysfunction (ED) <ref>[22]</ref>.<br \>
-There are 11 families of PDE (from 1 to 9), there is 21 genes for PDE which code 60 different PDE. For the PDE5A, the only PDE5 subcategory, there are 4 isoforms but their catalytic domain is the same [24].<br \>
+There are 11 families of PDE (from 1 to 9), there is 21 genes for PDE which code 60 different PDE. For the PDE5A, the only PDE5 subcategory, there are 4 isoforms but their catalytic domain is the same <ref>[24]</ref>.<br \>
 The catalytic reaction is the hydrolysis of guanosine cyclic monophosphate into linear guanosine monophosphate. This cGMP-specific enzyme have 3 domains (from N terminal to C terminal) : GAF A, GAF B and a conserved catalytic domain regard to other PDEs of the family. Only cGMP can bind GAF A or GAF B and it stimulates the hydrolysis.<br \>
-We study here the PDE5A catalytic fragment formed of amino acid residues from the 535th to the 860th [23]. In the inhibition, we talk about the Sildenafil mostly, because it's the most known (active ingredient in the Viagra®).<br \>
+We study here the PDE5A catalytic fragment formed of amino acid residues from the 535th to the 860th <ref>[23]</ref>. In the inhibition, we talk about the Sildenafil mostly, because it's the most known (active ingredient in the Viagra®).<br \>
 Problem in the PBD files: N-loop (from the 788th to the 881th residues) is not complete.
 == Structure of catalytic site ==
-The only catalytic fragment is effective, so the regulations sites and the dimerization to a trimeric enzyme are useless for the catalytic activity. Moreover, this catalytic moiety has the same activity that the wild-type enzyme, so maybe the enzyme is monomeric in the cell [24].
+The only catalytic fragment is effective, so the regulations sites and the dimerization to a trimeric enzyme are useless for the catalytic activity. Moreover, this catalytic moiety has the same activity that the wild-type enzyme, so maybe the enzyme is monomeric in the cell <ref>[24]</ref>.
-Catalytic domain is conserved for the PDE family, between 20% and 40%, and the variant reactions of the PDE inhibitors on the different PDEs may be caused by the more variant regulatory sites [25].<br \>
+Catalytic domain is conserved for the PDE family, between 20% and 40%, and the variant reactions of the PDE inhibitors on the different PDEs may be caused by the more variant regulatory sites <ref>[25]</ref>.<br \>
-The catalytic domain has 3 helical subdomains [24]:<br \>
+The catalytic domain has 3 helical subdomains <ref>[24]</ref>:<br \>
-* A N-terminal cyclin-fold region with eight helixes [26]: 5 α-helixes (1, 3, 5, 6 and 8) and 3 3ind10-helixes (2,4, and 7),<scene name='60/604476/537_678/3'> from the 537th to the 678th residues</scene>.<br \>
+* A N-terminal cyclin-fold region with eight helixes <ref>[26]</ref>: 5 α-helixes (1, 3, 5, 6 and 8) and 3 3ind10-helixes (2,4, and 7),<scene name='60/604476/537_678/3'> from the 537th to the 678th residues</scene>.<br \>
 * A linker domain: two antiparallels α9 and α10 helixes, and between a disordered region,<scene name='60/604476/679-725/2'>from the 679th to the 725th residues</scene>.<br \>
 * A C-terminal buddle pocket with eight helixes: 5 long α-helixes (11, 12, 14, 17 and 18) and 3 smaller helixes (13, 15 and 16),<scene name='60/604476/726-860/2'> from the 726th to the 860th residues</scene>.<br \>
 ** α5, 6 and 8 surround α3 and form an interface with the linker domain and the CTD.<br \>
-The catalytic site is a pocket which is 330Å in volume and a deep of 10Å, with a narrow entry. There are 4 regions: M (with 2 metallic ions), H (hydrophobic), Q (for the substrate), L (the lid or “H-Loop” on both N-term and linker domain). M site is surrounded by the helixes α6, 8, 9, 10 and 12. A majority of aliphatic or hydrophobic residues, that creates the hydrophobic pocket [2].<br \>
+The catalytic site is a pocket which is 330Å in volume and a deep of 10Å, with a narrow entry. There are 4 regions: M (with 2 metallic ions), H (hydrophobic), Q (for the substrate), L (the lid or “H-Loop” on both N-term and linker domain). M site is surrounded by the helixes α6, 8, 9, 10 and 12. A majority of aliphatic or hydrophobic residues, that creates the hydrophobic pocket <ref>[2]</ref>.<br \>
 M site contains:<br \>
-* The Me-1 and Me-2 sites are occupied by metal ions, Zinc within Me-1 and within Me-2, Zinc, Magnesium or Manganese [5],<br \>
+* The Me-1 and Me-2 sites are occupied by metal ions, Zinc within Me-1 and within Me-2, Zinc, Magnesium or Manganese <ref>[5]</ref>,<br \>
 * The residues <scene name='60/604476/His617_asp654_asp764_his653/1'>His617, Asp654, Asp764, His653</scene> and two H2O (W1 et W2) binding zinc:<br \>
 ** The crucial <scene name='60/604476/Asp764/1'>Asp764</scene> [3] and the conserved His617 and 653[4], which bind one Zinc ion, are fundamental for the catalytic activity.<br \>
@@ Line 43: / Line 43: @@
 == Inhibition ==
-In the treatment erection dysfunction, the inhibitors Sildenafil, Vardenafil and Tadalafil are used, like in the pulmonary hypertension[6]. Sildenafil may cure sleeping trouble after a intercontinental travel [11], may help to recover neural liaisons after an injury (the motor function[12] and the sensory motor function[13]) and can be vascular effects.<br \>[[Image:Sildenafil.jpg]]
+In the treatment erection dysfunction, the inhibitors Sildenafil, Vardenafil and Tadalafil are used, like in the pulmonary hypertension[6]. Sildenafil may cure sleeping trouble after a intercontinental travel [11], may help to recover neural liaisons after an injury (the motor function[12] and the sensory motor function[13]) and can be vascular effects.<br \>
 * PDE5 inhibitors might help physical condition in Duchene muscular dystrophy[14], improve of cognitive function [9]and have antidepressant effect[10] , also they might have an artero[15] and endothelial cell protective effect[16] so they have cardiac protection effect[17] (controversial, cf. clinical trial “RELAX”), finally they slow tumer cell growth (Tadalafil-like)[18]<br \>

Sandbox Reserved 957: Difference between revisions

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