2fm0

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(New page: 200px<br /> <applet load="2fm0" size="450" color="white" frame="true" align="right" spinBox="true" caption="2fm0, resolution 2.&Aring;" /> '''Crystal structure of ...)
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[[Image:2fm0.gif|left|200px]]<br />
 
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<applet load="2fm0" size="450" color="white" frame="true" align="right" spinBox="true"
 
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caption="2fm0, resolution 2.&Aring;" />
 
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'''Crystal structure of PDE4D in complex with L-869298'''<br />
 
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==Overview==
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==Crystal structure of PDE4D in complex with L-869298==
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Type 4 phosphodiesterase (PDE4) inhibitors are emerging as new treatments, for a number of disorders including asthma and chronic obstructive, pulmonary disease. Here we report the biochemical characterization on the, second generation inhibitor (+)-1 (L-, IC50=0.4 nM) and its enantiomer, (-)-1 (L-, IC50=43 nM) and their cocrystal structures with PDE4D at 2.0 A, resolution. Despite the 107-fold affinity difference, both enantiomers, interact with the same sets of residues in the rigid active site. The, weaker (-)-1 adopts an unfavorable conformation to preserve the pivotal, interactions between the Mg-bound waters and the N-oxide of pyridine., These structures support a model in which inhibitors are anchored by the, invariant glutamine at one end and the metal-pocket residues at another, end. This model provides explanations for most of the observed, structure-activity relationship and the metal ion dependency of the, catechol-ether based inhibitors and should facilitate their further, design.
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<StructureSection load='2fm0' size='340' side='right'caption='[[2fm0]], [[Resolution|resolution]] 2.00&Aring;' scene=''>
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== Structural highlights ==
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<table><tr><td colspan='2'>[[2fm0]] is a 4 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=2FM0 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2FM0 FirstGlance]. <br>
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</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=M98:(S)-3-(2-(3-CYCLOPROPOXY-4-(DIFLUOROMETHOXY)PHENYL)-2-(5-(1,1,1,3,3,3-HEXAFLUORO-2-HYDROXYPROPAN-2-YL)THIAZOL-2-YL)ETHYL)PYRIDINE+1-OXIDE'>M98</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=2fm0 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2fm0 OCA], [https://pdbe.org/2fm0 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2fm0 RCSB], [https://www.ebi.ac.uk/pdbsum/2fm0 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2fm0 ProSAT]</span></td></tr>
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</table>
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== Disease ==
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[https://www.uniprot.org/uniprot/PDE4D_HUMAN PDE4D_HUMAN] Note=Genetic variations in PDE4D might be associated with susceptibility to stroke. PubMed:17006457 states that association with stroke has to be considered with caution. Defects in PDE4D are the cause of acrodysostosis type 2, with or without hormone resistance (ACRDYS2) [MIM:[https://omim.org/entry/614613 614613]. ACRDYS2 is a pleiotropic disorder characterized by skeletal, endocrine, and neurological abnormalities. Skeletal features include brachycephaly, midface hypoplasia with a small upturned nose, brachydactyly, and lumbar spinal stenosis. Endocrine abnormalities include hypothyroidism and hypogonadism in males and irregular menses in females. Developmental disability is a common finding but is variable in severity and can be associated with significant behavioral problems.<ref>PMID:22464250</ref>
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== Function ==
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[https://www.uniprot.org/uniprot/PDE4D_HUMAN PDE4D_HUMAN] Hydrolyzes the second messenger cAMP, which is a key regulator of many important physiological processes.<ref>PMID:15260978</ref> <ref>PMID:15576036</ref>
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== Evolutionary Conservation ==
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[[Image:Consurf_key_small.gif|200px|right]]
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Check<jmol>
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<jmolCheckbox>
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<scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/fm/2fm0_consurf.spt"</scriptWhenChecked>
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<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
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<text>to colour the structure by Evolutionary Conservation</text>
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</jmolCheckbox>
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</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=2fm0 ConSurf].
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<div style="clear:both"></div>
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==Disease==
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==See Also==
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Known disease associated with this structure: Stroke, susceptibility to, 1 OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=600129 600129]]
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*[[Phosphodiesterase 3D structures|Phosphodiesterase 3D structures]]
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== References ==
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==About this Structure==
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<references/>
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2FM0 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 M98 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=2FM0 OCA].
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__TOC__
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</StructureSection>
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==Reference==
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Enantiomer discrimination illustrated by the high resolution crystal structures of type 4 phosphodiesterase., Huai Q, Sun Y, Wang H, Macdonald D, Aspiotis R, Robinson H, Huang Z, Ke H, J Med Chem. 2006 Mar 23;49(6):1867-73. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=16539372 16539372]
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[[Category: 3',5'-cyclic-nucleotide phosphodiesterase]]
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[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
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[[Category: Single protein]]
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[[Category: Large Structures]]
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[[Category: Aspiotis, R.]]
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[[Category: Aspiotis R]]
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[[Category: Huai, Q.]]
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[[Category: Huai Q]]
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[[Category: Huang, Z.]]
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[[Category: Huang Z]]
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[[Category: Ke, H.]]
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[[Category: Ke H]]
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[[Category: Macdonald, D.]]
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[[Category: Macdonald D]]
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[[Category: Robinson, H.]]
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[[Category: Robinson H]]
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[[Category: Sun, Y.]]
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[[Category: Sun Y]]
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[[Category: Wang, H.]]
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[[Category: Wang H]]
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[[Category: M98]]
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[[Category: MG]]
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[[Category: ZN]]
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[[Category: camp signalling]]
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[[Category: crystal structure]]
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[[Category: inhibitor selectivity]]
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[[Category: pde. enantiomer binding]]
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''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Mon Nov 12 22:07:24 2007''
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Current revision

Crystal structure of PDE4D in complex with L-869298

PDB ID 2fm0

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