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[[Image:2chm.gif|left|200px]]<br />
<applet load="2chm" size="450" color="white" frame="true" align="right" spinBox="true"
caption="2chm, resolution 1.6&Aring;" />
'''CRYSTAL STRUCTURE OF N2 SUBSTITUTED PYRAZOLO PYRIMIDINONES-A FLIPPED BINDING MODE IN PDE5'''<br />


==Overview==
==Crystal structure of N2 substituted pyrazolo pyrimidinones - a flipped binding mode in PDE5==
Sildenafil, (5-[2-ethoxy-5-(4-methyl-1-piperazinylsulfonyl)phenyl]-1-methyl-3-n-propyl, -1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one), a potent and selective, phosphodiesterase type 5 (PDE5) inhibitor, provided the first oral, treatment for male erectile dysfunction. The objective of the work, reported in this paper was to combine high levels of PDE5 potency and, selectivity with high and dose-independent oral bioavailability, to, minimize the impact on the C(max) of any interactions with coadministered, drugs in the clinic. This goal was achieved through identification of a, lower clearance series with a high absorption profile, by replacing the, 5'-piperazine sulfonamide in the sildenafil template with a 5'-methyl, ketone. This novel series provided compounds with low metabolism in ... [[http://ispc.weizmann.ac.il/pmbin/getpm?16759100 (full description)]]
<StructureSection load='2chm' size='340' side='right'caption='[[2chm]], [[Resolution|resolution]] 1.60&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[2chm]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2CHM OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2CHM FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.6&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=3P4:5-[2-(BUT-3-EN-1-YLOXY)-5-(1-HYDROXYVINYL)PYRIDIN-3-YL]-3-ETHYL-2-(1-ETHYLAZETIDIN-3-YL)-1,2,6,7A-TETRAHYDRO-7H-PYRAZOLO[4,3-D]PYRIMIDIN-7-ONE'>3P4</scene>, <scene name='pdbligand=MES:2-(N-MORPHOLINO)-ETHANESULFONIC+ACID'>MES</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=2chm FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2chm OCA], [https://pdbe.org/2chm PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2chm RCSB], [https://www.ebi.ac.uk/pdbsum/2chm PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2chm ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/PDE5A_HUMAN PDE5A_HUMAN] Plays a role in signal transduction by regulating the intracellular concentration of cyclic nucleotides. This phosphodiesterase catalyzes the specific hydrolysis of cGMP to 5'-GMP.[https://www.uniprot.org/uniprot/PDE4B_HUMAN PDE4B_HUMAN] Hydrolyzes the second messenger cAMP, which is a key regulator of many important physiological processes. May be involved in mediating central nervous system effects of therapeutic agents ranging from antidepressants to antiasthmatic and anti-inflammatory agents.<ref>PMID:10846163</ref> <ref>PMID:15003452</ref>
== Evolutionary Conservation ==
[[Image:Consurf_key_small.gif|200px|right]]
Check<jmol>
  <jmolCheckbox>
    <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/ch/2chm_consurf.spt"</scriptWhenChecked>
    <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
    <text>to colour the structure by Evolutionary Conservation</text>
  </jmolCheckbox>
</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=2chm ConSurf].
<div style="clear:both"></div>


==About this Structure==
==See Also==
2CHM is a [[http://en.wikipedia.org/wiki/Single_protein Single protein]] structure of sequence from [[http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]] with ZN, MG, 3P4 and MES as [[http://en.wikipedia.org/wiki/ligands ligands]]. Structure known Active Site: AC1. Full crystallographic information is available from [[http://ispc.weizmann.ac.il/oca-bin/ocashort?id=2CHM OCA]].
*[[Phosphodiesterase 3D structures|Phosphodiesterase 3D structures]]
 
== References ==
==Reference==
<references/>
A novel series of potent and selective PDE5 inhibitors with potential for high and dose-independent oral bioavailability., Allerton CM, Barber CG, Beaumont KC, Brown DG, Cole SM, Ellis D, Lane CA, Maw GN, Mount NM, Rawson DJ, Robinson CM, Street SD, Summerhill NW, J Med Chem. 2006 Jun 15;49(12):3581-94. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=16759100 16759100]
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
[[Category: Single protein]]
[[Category: Large Structures]]
[[Category: Allerton, C.M.N.]]
[[Category: Allerton CMN]]
[[Category: Barber, C.G.]]
[[Category: Barber CG]]
[[Category: Beaumont, K.C.]]
[[Category: Beaumont KC]]
[[Category: Brown, D.G.]]
[[Category: Brown DG]]
[[Category: Cole, S.M.]]
[[Category: Cole SM]]
[[Category: Ellis, D.]]
[[Category: Ellis D]]
[[Category: Lane, C.A.L.]]
[[Category: Lane CAL]]
[[Category: Maw, G.N.]]
[[Category: Maw GN]]
[[Category: Mount, N.M.]]
[[Category: Mount NM]]
[[Category: Rawson, D.J.]]
[[Category: Rawson DJ]]
[[Category: Robinson, C.M.]]
[[Category: Robinson CM]]
[[Category: Street, S.D.A.]]
[[Category: Street SDA]]
[[Category: Summerhill, N.W.]]
[[Category: Summerhill NW]]
[[Category: 3P4]]
[[Category: MES]]
[[Category: MG]]
[[Category: ZN]]
[[Category: allosteric enzyme]]
[[Category: alternative splicing]]
[[Category: camp]]
[[Category: cgmp]]
[[Category: cgmp-binding]]
[[Category: chimera]]
[[Category: hydrolase]]
[[Category: inhibitor]]
[[Category: magnesium]]
[[Category: metal-binding]]
[[Category: nucleotide-binding]]
[[Category: phosphodiesterase 5]]
[[Category: phosphorylation]]
[[Category: zinc]]
 
''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Tue Oct 30 13:25:35 2007''
Retrieved from "https://proteopedia.org/2chm"