Sandbox Reserved 957: Difference between revisions

** 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 \>

** <scene name='60/604476/Zn/1'>Zinc</scene> is critical for catalytic activity, but it isn't implied in the formation of the hydrophobic pocket. In fact, even if <scene name='60/604476/His653_his617/1'>the His617and 653</scene> are lost and so the Zn not bound, a massive addition of Manganese[4] in the medium allows a reactivation of catalysis.<br \>

* W2 binds <scene name='60/604476/Mg_zn/1'>Zn and Mg</scene> [24],<br \>

* And there are 3 hydrogen bonds between 3 H2O and the conserved resides <scene name='60/604476/His657glu682his685/1'>His657, Asp682 and His685</scene> [24].<br \>

* In particular the conserved residues <scene name='60/604476/Qsite1/1'>Gln817, Phe820, Val782 and Tyr612. [24]</scene><br \>

* The hydrogen bonds, between <scene name='60/604476/Qsite2/1'>Gln817 and 775, Gln775 and Ala767, Gln775 and Trp853</scene>, imply an interaction between <scene name='60/604476/Gln817/1'>Gln817</scene> and the cGMP purine. Thus, it improves the specificity for the cGMP, against cAMP. [24]<br \>

* And <scene name='60/604476/Qsite3/1'>Tyr612, Val782, Leu785 an Phe820</scene> bind the cGMP through this pyrazol ring and π-π interactions between Gln817 and the phenyl ring. [24]<br \>

** So, the conserved hydrophobic residue <scene name='60/604476/Tyr612/1'>Tyr 612</scene> is critical in the maintaining of the affinity. [3]<br \>

* In particular the residues <scene name='60/604476/Hsite1/1'>Phe786, Ala783, Leu804, Val782</scene>. [24]<br \>

* In particular the hydrophobic residues <scene name='60/604476/Lsite1/1'>Tyr664, Met816, Ala823, Gly819</scene>. [24]<br \>

Besides, the kcat of the catalytic fragment decreases 40-fold and 8-fold if the residues <scene name='60/604476/Lys603_leu644/1'>His603 and Asp644</scene> are mutated, and so there are important in the catalytic activity [5,3]. Two others residues are significant: <scene name='60/604476/Gln778/1'>the Gln778</scene> which is important for cGMP affinity but have no impact on cAMP affinity H-loop [8] and the conserved <scene name='60/604476/Gly659/1'>Gly659</scene> which is important for substrate affinity and catalytic activity because it determinates H-loop conformation [21] (see below).<br \>

H-loop is important in the substrate recognition and the interactions with, it is <scene name='60/604476/H_loop/1'>from 660th to 693th residues</scene>. H-loop has the same interactions with cGMP and Sildenafil (cf. Inhibitor) because it's related to its role of substrate binding[21]. But The H-loop is not well understood, because when it's modified, the enzyme's function is practically not modified.[7] But it also may have a role for inhibitor fixation.<br \>

Nowadays catalysis mechanism is not well know: there could be a, nucleophile attack of a water molecule on the substrate [6].

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|center|thumb|100px|Sildenafil Inhibitor, R1 in blue, R2 in green and R3 in red]]

* 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 \>