Sandbox Reserved 957: Difference between revisions
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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 \> | 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 [23]. 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 == | == Structure of catalytic site == | ||
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== Inhibition == | == 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 \> | 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 \> | * 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 \> | ||
* There are other PDE5 inhibitors: IBMX, Icarisid II and Udenafil.<br \> | * There are other PDE5 inhibitors: IBMX, Icarisid II and Udenafil.<br \> | ||
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H-loop:<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 the N-loop (788-811) ):<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. [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 | * 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 \> | ||
* H-loop is less important in the interactions for Sildenafil and Icarisid II than cGMP.<br \> | * H-loop is less important in the interactions for Sildenafil and Icarisid II than cGMP.<br \> | ||