3d3p

From Proteopedia

(Difference between revisions)

Current revision

Crystal structure of PDE4B catalytic domain in complex with a pyrazolopyridine inhibitor

Structural highlights

3d3p 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 1.75Å
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

Optimisation of a high-throughput screening hit resulted in the discovery of 4-(substituted amino)-1-alkyl-pyrazolo[3,4-b]pyridine-5-carboxamides as potent and selective inhibitors of Phosphodiesterase 4 (PDE4). Herein, we describe early SAR studies around this novel template highlighting preferred substituents and rationalization of SAR through X-ray crystal structures of analogues bound to the PDE4 active site. Pyrazolopyridine 20a was found to be a potent and selective PDE4 inhibitor which also inhibits LPS induced TNF-alpha production from isolated human peripheral blood mononuclear cells and has an encouraging rat PK profile suitable for oral dosing.

Pyrazolopyridines as a novel structural class of potent and selective PDE4 inhibitors.,Hamblin JN, Angell TD, Ballantine SP, Cook CM, Cooper AW, Dawson J, Delves CJ, Jones PS, Lindvall M, Lucas FS, Mitchell CJ, Neu MY, Ranshaw LE, Solanke YE, Somers DO, Wiseman JO Bioorg Med Chem Lett. 2008 Jul 15;18(14):4237-41. Epub 2008 May 17. PMID:18539455^[3]

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

References

↑ 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
↑ 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
↑ Hamblin JN, Angell TD, Ballantine SP, Cook CM, Cooper AW, Dawson J, Delves CJ, Jones PS, Lindvall M, Lucas FS, Mitchell CJ, Neu MY, Ranshaw LE, Solanke YE, Somers DO, Wiseman JO. Pyrazolopyridines as a novel structural class of potent and selective PDE4 inhibitors. Bioorg Med Chem Lett. 2008 Jul 15;18(14):4237-41. Epub 2008 May 17. PMID:18539455 doi:10.1016/j.bmcl.2008.05.052

1 Structural highlights
2 Function
3 Evolutionary Conservation
4 Publication Abstract from PubMed
5 See Also
6 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/3d3p"

Categories: Homo sapiens | Large Structures | Neu M | Somers DO

@@ Line 3: / Line 3: @@
 <StructureSection load='3d3p' size='340' side='right'caption='[[3d3p]], [[Resolution|resolution]] 1.75&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[3d3p]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3D3P OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3D3P FirstGlance]. <br>
+<table><tr><td colspan='2'>[[3d3p]] 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=3D3P OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3D3P FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=20A:1-ETHYL-N-(PHENYLMETHYL)-4-(TETRAHYDRO-2H-PYRAN-4-YLAMINO)-1H-PYRAZOLO[3,4-B]PYRIDINE-5-CARBOXAMIDE'>20A</scene>, <scene name='pdbligand=ARS:ARSENIC'>ARS</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.75&#8491;</td></tr>
-<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">PDE4B, DPDE4 ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=20A:1-ETHYL-N-(PHENYLMETHYL)-4-(TETRAHYDRO-2H-PYRAN-4-YLAMINO)-1H-PYRAZOLO[3,4-B]PYRIDINE-5-CARBOXAMIDE'>20A</scene>, <scene name='pdbligand=ARS:ARSENIC'>ARS</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
-<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/3',5'-cyclic-nucleotide_phosphodiesterase 3',5'-cyclic-nucleotide phosphodiesterase], with EC number [https://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.1.4.17 3.1.4.17] </span></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=3d3p FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3d3p OCA], [https://pdbe.org/3d3p PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3d3p RCSB], [https://www.ebi.ac.uk/pdbsum/3d3p PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3d3p 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>
+[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]]
@@ Line 37: / Line 36: @@
 __TOC__
 </StructureSection>
-[[Category: 3',5'-cyclic-nucleotide phosphodiesterase]]
+[[Category: Homo sapiens]]
-[[Category: Human]]
 [[Category: Large Structures]]
-[[Category: Neu, M]]
+[[Category: Neu M]]
-[[Category: Somers, D O]]
+[[Category: Somers DO]]
-[[Category: Alternative splicing]]
-[[Category: Camp]]
-[[Category: Hydrolase]]
-[[Category: Pde]]
-[[Category: Phosphodiesterase]]
-[[Category: Phosphoprotein]]
-[[Category: Polymorphism]]

3d3p

From Proteopedia

Current revision

Crystal structure of PDE4B catalytic domain in complex with a pyrazolopyridine inhibitor

Structural highlights

Function

Evolutionary Conservation

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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