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[[Image:3o57.jpg|left|200px]]


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==Catalytic domain of human phosphodiesterase 4b2b in complex with a 5-heterocycle pyrazolopyridine inhibitor==
The line below this paragraph, containing "STRUCTURE_3o57", creates the "Structure Box" on the page.
<StructureSection load='3o57' size='340' side='right'caption='[[3o57]], [[Resolution|resolution]] 2.00&Aring;' scene=''>
You may change the PDB parameter (which sets the PDB file loaded into the applet)
== Structural highlights ==
or the SCENE parameter (which sets the initial scene displayed when the page is loaded),
<table><tr><td colspan='2'>[[3o57]] 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=3O57 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3O57 FirstGlance]. <br>
or leave the SCENE parameter empty for the default display.
</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&#8491;</td></tr>
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ARS:ARSENIC'>ARS</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=ZG2:5-[5-BENZYL-4-(2-OXO-2-PYRROLIDIN-1-YLETHYL)-1,3-OXAZOL-2-YL]-1-ETHYL-N-(TETRAHYDRO-2H-PYRAN-4-YL)-1H-PYRAZOLO[3,4-B]PYRIDIN-4-AMINE'>ZG2</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
{{STRUCTURE_3o57|  PDB=3o57  |  SCENE=  }}
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=3o57 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3o57 OCA], [https://pdbe.org/3o57 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3o57 RCSB], [https://www.ebi.ac.uk/pdbsum/3o57 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3o57 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>
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Following the discovery of 4-(substituted amino)-1-alkyl-pyrazolo[3,4-b]pyridine-5-carboxamides as potent and selective phosphodiesterase 4B inhibitors, [Hamblin, J. N.; Angell, T.; Ballentine, S., et al. Bioorg. Med. Chem. Lett.2008, 18, 4237] the SAR of the 5-position was investigated further. A range of substituted heterocycles showed good potencies against PDE4. Optimisation using X-ray crystallography and computational modelling led to the discovery of 16, with sub-nM inhibition of LPS-induced TNF-alpha production from isolated human peripheral blood mononuclear cells.


===Catalytic domain of human phosphodiesterase 4b2b in complex with a 5-heterocycle pyrazolopyridine inhibitor===
Pyrazolopyridines as potent PDE4B inhibitors: 5-heterocycle SAR.,Mitchell CJ, Ballantine SP, Coe DM, Cook CM, Delves CJ, Dowle MD, Edlin CD, Hamblin JN, Holman S, Johnson MR, Jones PS, Keeling SE, Kranz M, Lindvall M, Lucas FS, Neu M, Solanke YE, Somers DO, Trivedi NA, Wiseman JO Bioorg Med Chem Lett. 2010 Oct 1;20(19):5803-6. Epub 2010 Aug 5. PMID:20732811<ref>PMID:20732811</ref>


From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 3o57" style="background-color:#fffaf0;"></div>


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==See Also==
The line below this paragraph, {{ABSTRACT_PUBMED_20732811}}, adds the Publication Abstract to the page
*[[Phosphodiesterase 3D structures|Phosphodiesterase 3D structures]]
(as it appears on PubMed at http://www.pubmed.gov), where 20732811 is the PubMed ID number.
== References ==
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<references/>
{{ABSTRACT_PUBMED_20732811}}
__TOC__
 
</StructureSection>
==About this Structure==
[[3o57]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3O57 OCA].
 
==Reference==
<ref group="xtra">PMID:020732811</ref><references group="xtra"/>
[[Category: 3',5'-cyclic-nucleotide phosphodiesterase]]
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
[[Category: Neu, M.]]
[[Category: Large Structures]]
[[Category: Somers, D O.]]
[[Category: Neu M]]
[[Category: Camp binding]]
[[Category: Somers DO]]
[[Category: Hydrolase]]
[[Category: Hydrolase-hydrolase inhibitor complex]]
[[Category: Pde]]
[[Category: Phosphodiesterase]]

Latest revision as of 12:27, 6 September 2023

Catalytic domain of human phosphodiesterase 4b2b in complex with a 5-heterocycle pyrazolopyridine inhibitorCatalytic domain of human phosphodiesterase 4b2b in complex with a 5-heterocycle pyrazolopyridine inhibitor

Structural highlights

3o57 is a 1 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 2Å
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]

Publication Abstract from PubMed

Following the discovery of 4-(substituted amino)-1-alkyl-pyrazolo[3,4-b]pyridine-5-carboxamides as potent and selective phosphodiesterase 4B inhibitors, [Hamblin, J. N.; Angell, T.; Ballentine, S., et al. Bioorg. Med. Chem. Lett.2008, 18, 4237] the SAR of the 5-position was investigated further. A range of substituted heterocycles showed good potencies against PDE4. Optimisation using X-ray crystallography and computational modelling led to the discovery of 16, with sub-nM inhibition of LPS-induced TNF-alpha production from isolated human peripheral blood mononuclear cells.

Pyrazolopyridines as potent PDE4B inhibitors: 5-heterocycle SAR.,Mitchell CJ, Ballantine SP, Coe DM, Cook CM, Delves CJ, Dowle MD, Edlin CD, Hamblin JN, Holman S, Johnson MR, Jones PS, Keeling SE, Kranz M, Lindvall M, Lucas FS, Neu M, Solanke YE, Somers DO, Trivedi NA, Wiseman JO Bioorg Med Chem Lett. 2010 Oct 1;20(19):5803-6. Epub 2010 Aug 5. PMID:20732811[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. ↑ Mitchell CJ, Ballantine SP, Coe DM, Cook CM, Delves CJ, Dowle MD, Edlin CD, Hamblin JN, Holman S, Johnson MR, Jones PS, Keeling SE, Kranz M, Lindvall M, Lucas FS, Neu M, Solanke YE, Somers DO, Trivedi NA, Wiseman JO. Pyrazolopyridines as potent PDE4B inhibitors: 5-heterocycle SAR. Bioorg Med Chem Lett. 2010 Oct 1;20(19):5803-6. Epub 2010 Aug 5. PMID:20732811 doi:10.1016/j.bmcl.2010.07.136

3o57, resolution 2.00Å

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