1xon: Difference between revisions

Proteopedia Page Contributors and Editors (what is this?)Proteopedia Page Contributors and Editors (what is this?)

OCA

@@ Line 1: / Line 1: @@
-[[Image:1xon.gif|left|200px]]<br />
-<applet load="1xon" size="450" color="white" frame="true" align="right" spinBox="true"
-caption="1xon, resolution 1.72&Aring;" />
-'''Catalytic Domain Of Human Phosphodiesterase 4D In Complex With Piclamilast'''<br />
-==Overview==
+==Catalytic Domain Of Human Phosphodiesterase 4D In Complex With Piclamilast==
-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='1xon' size='340' side='right'caption='[[1xon]], [[Resolution|resolution]] 1.72&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[1xon]] 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=1XON OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1XON 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]] 1.72&#8491;</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=B3P:2-[3-(2-HYDROXY-1,1-DIHYDROXYMETHYL-ETHYLAMINO)-PROPYLAMINO]-2-HYDROXYMETHYL-PROPANE-1,3-DIOL'>B3P</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=PIL:3-(CYCLOPENTYLOXY)-N-(3,5-DICHLOROPYRIDIN-4-YL)-4-METHOXYBENZAMIDE'>PIL</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=1xon FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1xon OCA], [https://pdbe.org/1xon PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1xon RCSB], [https://www.ebi.ac.uk/pdbsum/1xon PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1xon ProSAT]</span></td></tr>
+</table>
+== Disease ==
+[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>
+== Function ==
+[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>
+== 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/1xon_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=1xon ConSurf].
+<div style="clear:both"></div>
-==Disease==
+==See Also==
-Known disease associated with this structure: Stroke, susceptibility to, 1 OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=600129 600129]]
+*[[Phosphodiesterase 3D structures|Phosphodiesterase 3D structures]]
+== References ==
-==About this Structure==
+<references/>
-XON 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, PIL, B3P and EDO 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=1XON OCA].
+__TOC__
+</StructureSection>
-==Reference==
-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]
-[[Category: 3',5'-cyclic-nucleotide phosphodiesterase]]
 [[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: B3P]]
-[[Category: EDO]]
-[[Category: MG]]
-[[Category: PIL]]
-[[Category: ZN]]
-[[Category: pde]]
-[[Category: pde4d]]
-[[Category: phosphodiesterase]]
-[[Category: piclamilast]]
-''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Mon Nov 12 20:08:39 2007''