This old version of Proteopedia is provided for student assignments while the new version is undergoing repairs. Content and edits done in this old version of Proteopedia after March 1, 2026 will eventually be lost when it is retired in about June of 2026.

Apply for new accounts at the new Proteopedia. Your logins will work in both the old and new versions.


Sandbox Reserved 1127

From Proteopedia

(Difference between revisions)
Jump to: navigation, search
Line 12: Line 12:
== Structural highlights ==
== Structural highlights ==
-
PDE5 is a dimeric protein of about 270 amino acids long. The C terminal has the catalytic domain and two Zn2+ binding site and N temrinal is the regulatory domain which includes two the GAF domain a and b. There are thus plural allosteric binding site for cGMP in the Cterminal and the N terminal. cGAMP binds on Gap an allosteric site and promotes the phosphorylation of SER 92 of PKG. This phosphorylation increases the affinity between cGMP and PDE5. Another cGMP can bind to the Gap b which allows the activation of the catalytic site of PDE5. The activated catalytic site is now able to break the phosphodiesteric bond of cGMP :http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2518390/)
+
PDE5 is a homodimeric protein of 875 amino acids long. This protein is composed of several important domains:
 +
pol-GLY (10-24 amino acids) in Ntermini (structural importance).
 +
GAFA (164-314 amino acids)
 +
GAFB (346-503 amino acids)
 +
Catalytic domain (588-853 amino acids) in Ctermini involved in cGMP hydrolysis.
 +
The full structure of PDE5 has not been crystallized contrary to this of isolated domains of the protein.
 +
GAFA and GAFB are homologous domains and allosteric binding site of cGMP.
==Catalytic activity==
==Catalytic activity==
 +
PDE5 is a phosphodiesterase. cGMP could bind the catalytic domain thanks to hydrogen bonds made with Gln775 and Gln817 and coordination bonds made with Zn2+ and Mg2+ in the catalytic site. To see these interactions, report to Sildenafil in Inhibitors and medical application.
 +
cGMP is hydrolyzed in GMP. The catalytic chemical reaction deals with breaking a phosphodiester bound in cGMP between the 3'O of the guanoside and the phosphate of cGMP: cGMP + H20 => GMP.
Some residues could be affected by post traductional modifications :
Some residues could be affected by post traductional modifications :
-
- phosphorylation : S60, S86, S92, S102, S104, S108, T111, T127, T137, S869
+
phosphorylation : S60, S86, S92, S102, S104, S108, T111, T127, T137, S869.
-
- acylation : K364
+
acylation : K364.
-
- ubiquitinylation : K714
+
ubiquitinylation : K714.
-
 
+
The ubiquitinylation of <scene name='71/719868/K714/1'>K714</scene> (in fushia) and the phosphorylation of are involved in the binding of cGMP to PDE5 catalytic domain.
The ubiquitinylation of <scene name='71/719868/K714/1'>K714</scene> (in fushia) and the phosphorylation of are involved in the binding of cGMP to PDE5 catalytic domain.
== Inhibitors and medical application ==
== Inhibitors and medical application ==
-
If an inhibitor binds instead of cGMP, cGMP concentration increases and the stimulus continues. PDE5 inhibition is particulary used for erectile disfunction.
 
-
Sildenafil or VIagra is an inhibitor of PDE5.
 
-
GLN 775 and GLN 817 of PDE5 interacts through hydrogen bonds with <scene name='71/719868/Sildenafil/1'>Sildenafil</scene>
+
Inhibitors of PDE5 prevent cGMP from binding the catalytic site by competititve inhibition. They have more affinity for this domain than cGMP.
 +
Sildenafil (active substance of Viagra) binds to PDE5 catalytic domain through:
 +
hydrogen bonds made between Gln775 and Gln817 of PDE5 (green) and <scene name='71/719868/Sildenafil/1'>Sildenafil</scene> (red)
 +
coordination bond made with
 +
coordination made with
 +
 
==Allosteric activation==
==Allosteric activation==

Revision as of 16:57, 30 January 2016

This Sandbox is Reserved from 15/12/2015, through 15/06/2016 for use in the course "Structural Biology" taught by Bruno Kieffer at the University of Strasbourg, ESBS. This reservation includes Sandbox Reserved 1120 through Sandbox Reserved 1159.
To get started:
  • Click the edit this page tab at the top. Save the page after each step, then edit it again.
  • Click the 3D button (when editing, above the wikitext box) to insert Jmol.
  • show the Scene authoring tools, create a molecular scene, and save it. Copy the green link into the page.
  • Add a description of your scene. Use the buttons above the wikitext box for bold, italics, links, headlines, etc.

More help: Help:Editing

Human PDE5

PDE5 and its inhibitor Sildenafil

Drag the structure with the mouse to rotate

References

Retrieved from "http://52.214.119.220/wiki/index.php/Sandbox_Reserved_1127"
Personal tools