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Sandbox Reserved 957: Difference between revisions

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- A linker domain: two antiparallels α9 and α10 helixes, and between a disordered region, from the 679th to the 725th residues.
- A linker domain: two antiparallels α9 and α10 helixes, and between a disordered region, from the 679th to the 725th residues.
- 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), from the 726th to the 860th residues.
- 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), from the 726th to the 860th residues.
    > α5, 6 and 8 surround α3 and form an interface with the linker domain and the CTD.
> 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 [2].
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- 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 [5],
- The residues His617, Asp654, Asp764, His653 and two H2O (W1 et W2) binding zinc:
- The residues His617, Asp654, Asp764, His653 and two H2O (W1 et W2) binding zinc:
    + The crucial Asp764 [3] and the conserved His617 and 653[4], which bind one Zinc ion, are fundamental for the catalytic activity.
> The crucial Asp764 [3] and the conserved His617 and 653[4], which bind one Zinc ion, are fundamental for the catalytic activity.
    + Zinc is critical for catalytic activity, but it isn't implied in the formation of the hydrophobic pocket. In fact, even if the His617and 653 are lost and so the Zn not bound, a massive addition of Manganese[4] in the medium allows a reactivation of catalysis.
> Zinc is critical for catalytic activity, but it isn't implied in the formation of the hydrophobic pocket. In fact, even if the His617and 653 are lost and so the Zn not bound, a massive addition of Manganese[4] in the medium allows a reactivation of catalysis.
- W2 binds Zn and Mg [24],
- W2 binds Zn and Mg [24],
- And there are 3 hydrogen bonds between 3 H2O and the conserved resides His657, Asp682 and His685 [24].
- And there are 3 hydrogen bonds between 3 H2O and the conserved resides His657, Asp682 and His685 [24].
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- The hydrogen bonds, between Gln817 and 775, Gln775 and Ala767, Gln775 and Trp853, imply an interaction between Gln817 and the cGMP purine. Thus, it improves the specificity for the cGMP, against cAMP. [24]
- The hydrogen bonds, between Gln817 and 775, Gln775 and Ala767, Gln775 and Trp853, imply an interaction between Gln817 and the cGMP purine. Thus, it improves the specificity for the cGMP, against cAMP. [24]
- And Tyr612, Val782, Leu785 an Phe820 bind the cGMP through this pyrazol ring and π-π interactions between Gln817 and the phenyl ring. [24]
- And Tyr612, Val782, Leu785 an Phe820 bind the cGMP through this pyrazol ring and π-π interactions between Gln817 and the phenyl ring. [24]
    + So, the conserved hydrophobic residue Tyr 612 is critical in the maintaining of the affinity. [3]
> So, the conserved hydrophobic residue Tyr 612 is critical in the maintaining of the affinity. [3]


H site:
H site:
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H-loop:
H-loop:
- For each inhibitor, H-loop take a different and originally (comparatively to other PDEs) tertiary structure (and there are also minor modifications of the N-loop (788-811) ):
- For each inhibitor, H-loop take a different and originally (comparatively to other PDEs) tertiary structure (and there are also minor modifications of the N-loop (788-811) ):
    + For an unliganded PDE5, H-loop take a coil conformation. [21]
> For an unliganded PDE5, H-loop take a coil conformation. [21]
    + In case of Sildenafil binding, a turn and an 310 helix (from 672 to 675) appear, and residues from 668 to 676 are disordered. 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]
> In case of Sildenafil binding, a turn and an 310 helix (from 672 to 675) appear, and residues from 668 to 676 are disordered. 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]
    + H-loop is less important in the interactions for Sildenafil and Icarisid II than cGMP.
> H-loop is less important in the interactions for Sildenafil and Icarisid II than cGMP.


== Regulation ==
== Regulation ==

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OCA, Michael Pierrelee
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