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New page: left|200px<br /> <applet load="1xot" size="450" color="white" frame="true" align="right" spinBox="true" caption="1xot, resolution 2.34Å" /> '''Catalytic Domain Of...
 
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[[Image:1xot.gif|left|200px]]<br />
<applet load="1xot" size="450" color="white" frame="true" align="right" spinBox="true"
caption="1xot, resolution 2.34&Aring;" />
'''Catalytic Domain Of Human Phosphodiesterase 4B In Complex With Vardenafil'''<br />


==Overview==
==Catalytic Domain Of Human Phosphodiesterase 4B In Complex With Vardenafil==
Phosphodiesterases (PDEs) comprise a large family of enzymes that catalyze, the hydrolysis of cAMP or cGMP and are implicated in various diseases. We, describe the high-resolution crystal structures of the catalytic domains, of PDE4B, PDE4D, and PDE5A with ten different inhibitors, including the, drug candidates cilomilast and roflumilast, for respiratory diseases., These cocrystal structures reveal a common scheme of inhibitor binding to, the PDEs: (i) a hydrophobic clamp formed by highly conserved hydrophobic, residues that sandwich the inhibitor in the active site; (ii) hydrogen, bonding to an invariant glutamine that controls the orientation of, inhibitor binding. A scaffold can be readily identified for any given, inhibitor based on the formation of these two types of conserved, interactions. These structural insights will enable the design of, isoform-selective inhibitors with improved binding affinity and should, facilitate the discovery of more potent and selective PDE inhibitors for, the treatment of a variety of diseases.
<StructureSection load='1xot' size='340' side='right'caption='[[1xot]], [[Resolution|resolution]] 2.34&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[1xot]] is a 2 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=1XOT OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1XOT 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]] 2.34&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CME:S,S-(2-HYDROXYETHYL)THIOCYSTEINE'>CME</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=VDN:2-{2-ETHOXY-5-[(4-ETHYLPIPERAZIN-1-YL)SULFONYL]PHENYL}-5-METHYL-7-PROPYLIMIDAZO[5,1-F][1,2,4]TRIAZIN-4(1H)-ONE'>VDN</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=1xot FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1xot OCA], [https://pdbe.org/1xot PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1xot RCSB], [https://www.ebi.ac.uk/pdbsum/1xot PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1xot ProSAT]</span></td></tr>
</table>
== Function ==
[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/xo/1xot_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=1xot ConSurf].
<div style="clear:both"></div>
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Phosphodiesterases (PDEs) comprise a large family of enzymes that catalyze the hydrolysis of cAMP or cGMP and are implicated in various diseases. We describe the high-resolution crystal structures of the catalytic domains of PDE4B, PDE4D, and PDE5A with ten different inhibitors, including the drug candidates cilomilast and roflumilast, for respiratory diseases. These cocrystal structures reveal a common scheme of inhibitor binding to the PDEs: (i) a hydrophobic clamp formed by highly conserved hydrophobic residues that sandwich the inhibitor in the active site; (ii) hydrogen bonding to an invariant glutamine that controls the orientation of inhibitor binding. A scaffold can be readily identified for any given inhibitor based on the formation of these two types of conserved interactions. These structural insights will enable the design of isoform-selective inhibitors with improved binding affinity and should facilitate the discovery of more potent and selective PDE inhibitors for the treatment of a variety of diseases.


==About this Structure==
Structural basis for the activity of drugs that inhibit phosphodiesterases.,Card GL, England BP, Suzuki Y, Fong D, Powell B, Lee B, Luu C, Tabrizizad M, Gillette S, Ibrahim PN, Artis DR, Bollag G, Milburn MV, Kim SH, Schlessinger J, Zhang KY Structure. 2004 Dec;12(12):2233-47. PMID:15576036<ref>PMID:15576036</ref>
1XOT 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 and VDN as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/3',5'-cyclic-nucleotide_phosphodiesterase 3',5'-cyclic-nucleotide phosphodiesterase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.1.4.17 3.1.4.17] Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=1XOT OCA].


==Reference==
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
Structural basis for the activity of drugs that inhibit phosphodiesterases., Card GL, England BP, Suzuki Y, Fong D, Powell B, Lee B, Luu C, Tabrizizad M, Gillette S, Ibrahim PN, Artis DR, Bollag G, Milburn MV, Kim SH, Schlessinger J, Zhang KY, Structure. 2004 Dec;12(12):2233-47. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=15576036 15576036]
</div>
[[Category: 3',5'-cyclic-nucleotide phosphodiesterase]]
<div class="pdbe-citations 1xot" style="background-color:#fffaf0;"></div>
 
==See Also==
*[[Phosphodiesterase 3D structures|Phosphodiesterase 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
[[Category: Single protein]]
[[Category: Large Structures]]
[[Category: Artis, D.R.]]
[[Category: Artis DR]]
[[Category: Bollag, G.]]
[[Category: Bollag G]]
[[Category: Card, G.L.]]
[[Category: Card GL]]
[[Category: England, B.P.]]
[[Category: England BP]]
[[Category: Fong, D.]]
[[Category: Fong D]]
[[Category: Gillette, S.]]
[[Category: Gillette S]]
[[Category: Ibrahim, P.N.]]
[[Category: Ibrahim PN]]
[[Category: Kim, S.H.]]
[[Category: Kim S-H]]
[[Category: Lee, B.]]
[[Category: Lee B]]
[[Category: Luu, C.]]
[[Category: Luu C]]
[[Category: Milburn, M.V.]]
[[Category: Milburn MV]]
[[Category: Powell, B.]]
[[Category: Powell B]]
[[Category: Schlessinger, J.]]
[[Category: Schlessinger J]]
[[Category: Suzuki, Y.]]
[[Category: Suzuki Y]]
[[Category: Tabrizizad, M.]]
[[Category: Tabrizizad M]]
[[Category: Zhang, K.Y.J.]]
[[Category: Zhang KYJ]]
[[Category: MG]]
[[Category: VDN]]
[[Category: ZN]]
[[Category: levitra]]
[[Category: pde]]
[[Category: pde4b]]
[[Category: phosphodiesterase]]
[[Category: vardenafil]]
 
''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Mon Nov 12 20:08:51 2007''

Latest revision as of 10:56, 15 May 2024

Catalytic Domain Of Human Phosphodiesterase 4B In Complex With VardenafilCatalytic Domain Of Human Phosphodiesterase 4B In Complex With Vardenafil

Structural highlights

1xot is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 2.34Å
Ligands:, , ,
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

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.[1] [2]

Evolutionary Conservation

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

Publication Abstract from PubMed

Phosphodiesterases (PDEs) comprise a large family of enzymes that catalyze the hydrolysis of cAMP or cGMP and are implicated in various diseases. We describe the high-resolution crystal structures of the catalytic domains of PDE4B, PDE4D, and PDE5A with ten different inhibitors, including the drug candidates cilomilast and roflumilast, for respiratory diseases. These cocrystal structures reveal a common scheme of inhibitor binding to the PDEs: (i) a hydrophobic clamp formed by highly conserved hydrophobic residues that sandwich the inhibitor in the active site; (ii) hydrogen bonding to an invariant glutamine that controls the orientation of inhibitor binding. A scaffold can be readily identified for any given inhibitor based on the formation of these two types of conserved interactions. These structural insights will enable the design of isoform-selective inhibitors with improved binding affinity and should facilitate the discovery of more potent and selective PDE inhibitors for the treatment of a variety of diseases.

Structural basis for the activity of drugs that inhibit phosphodiesterases.,Card GL, England BP, Suzuki Y, Fong D, Powell B, Lee B, Luu C, Tabrizizad M, Gillette S, Ibrahim PN, Artis DR, Bollag G, Milburn MV, Kim SH, Schlessinger J, Zhang KY Structure. 2004 Dec;12(12):2233-47. PMID:15576036[3]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

See Also

References

  1. ↑ Xu RX, Hassell AM, Vanderwall D, Lambert MH, Holmes WD, Luther MA, Rocque WJ, Milburn MV, Zhao Y, Ke H, Nolte RT. Atomic structure of PDE4: insights into phosphodiesterase mechanism and specificity. Science. 2000 Jun 9;288(5472):1822-5. PMID:10846163
  2. ↑ Xu RX, Rocque WJ, Lambert MH, Vanderwall DE, Luther MA, Nolte RT. Crystal structures of the catalytic domain of phosphodiesterase 4B complexed with AMP, 8-Br-AMP, and rolipram. J Mol Biol. 2004 Mar 19;337(2):355-65. PMID:15003452 doi:http://dx.doi.org/10.1016/j.jmb.2004.01.040
  3. ↑ Card GL, England BP, Suzuki Y, Fong D, Powell B, Lee B, Luu C, Tabrizizad M, Gillette S, Ibrahim PN, Artis DR, Bollag G, Milburn MV, Kim SH, Schlessinger J, Zhang KY. Structural basis for the activity of drugs that inhibit phosphodiesterases. Structure. 2004 Dec;12(12):2233-47. PMID:15576036 doi:http://dx.doi.org/10.1016/j.str.2004.10.004

1xot, resolution 2.34Å

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