3gwt

Catalytic domain of human phosphodiesterase 4B2B in complex with a quinoline inhibitorCatalytic domain of human phosphodiesterase 4B2B in complex with a quinoline inhibitor

Structural highlights

3gwt 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

Crystallography driven optimisation of a lead derived from similarity searching of the GSK compound collection resulted in the discovery of quinoline-3-carboxamides as highly potent and selective inhibitors of phosphodiesterase 4B. This series has been optimized to GSK256066, a potent PDE4B inhibitor which also inhibits LPS induced production of TNF-alpha from isolated human peripheral blood mononuclear cells with a pIC(50) of 11.1. GSK256066 also has a suitable profile for inhaled dosing.

Quinolines as a novel structural class of potent and selective PDE4 inhibitors. Optimisation for inhaled administration.,Woodrow MD, Ballantine SP, Barker MD, Clarke BJ, Dawson J, Dean TW, Delves CJ, Evans B, Gough SL, Guntrip SB, Holman S, Holmes DS, Kranz M, Lindvaal MK, Lucas FS, Neu M, Ranshaw LE, Solanke YE, Somers DO, Ward P, Wiseman JO Bioorg Med Chem Lett. 2009 Sep 1;19(17):5261-5. Epub 2009 Apr 9. PMID:19656678^[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
↑ Woodrow MD, Ballantine SP, Barker MD, Clarke BJ, Dawson J, Dean TW, Delves CJ, Evans B, Gough SL, Guntrip SB, Holman S, Holmes DS, Kranz M, Lindvaal MK, Lucas FS, Neu M, Ranshaw LE, Solanke YE, Somers DO, Ward P, Wiseman JO. Quinolines as a novel structural class of potent and selective PDE4 inhibitors. Optimisation for inhaled administration. Bioorg Med Chem Lett. 2009 Sep 1;19(17):5261-5. Epub 2009 Apr 9. PMID:19656678 doi:10.1016/j.bmcl.2009.04.012

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OCA

[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] Woodrow MD, Ballantine SP, Barker MD, Clarke BJ, Dawson J, Dean TW, Delves CJ, Evans B, Gough SL, Guntrip SB, Holman S, Holmes DS, Kranz M, Lindvaal MK, Lucas FS, Neu M, Ranshaw LE, Solanke YE, Somers DO, Ward P, Wiseman JO. Quinolines as a novel structural class of potent and selective PDE4 inhibitors. Optimisation for inhaled administration. Bioorg Med Chem Lett. 2009 Sep 1;19(17):5261-5. Epub 2009 Apr 9. PMID:19656678 doi:10.1016/j.bmcl.2009.04.012

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