1qxl

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(New page: 200px<br /><applet load="1qxl" size="450" color="white" frame="true" align="right" spinBox="true" caption="1qxl, resolution 2.25&Aring;" /> '''Crystal structure of...)
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[[Image:1qxl.jpg|left|200px]]<br /><applet load="1qxl" size="450" color="white" frame="true" align="right" spinBox="true"
 
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caption="1qxl, resolution 2.25&Aring;" />
 
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'''Crystal structure of Adenosine deaminase complexed with FR235380'''<br />
 
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==Overview==
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==Crystal structure of Adenosine deaminase complexed with FR235380==
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We disclose herein optimization efforts around the novel, highly potent, non-nucleoside adenosine deaminase (ADA) inhibitor, 1-[(R)-1-hydroxy-4-(6-(3-(1-methylbenzimidazol-2-yl)propionylamino)indol-1, -yl)-2-butyl]imidazole-4-carboxamide 1 (K(i)= 7.7 nM), which we recently, reported. Structure-based drug design (SBDD) utilizing the crystal, structure of the 1/ADA complex was performed in order to obtain, structure-activity relationships (SAR) for this type of compound, rationally and effectively. To utilize the newly formed hydrophobic space, (F2), replacement of the benzimidazole ring of 1 with a n-propyl chain, (4b) or a simple phenyl ring (4c) was tolerated in terms of binding, activity, and the length of the methylene-spacer was shown to be optimal, at two or three. Replacement of an amide with an ether as a linker was, also well tolerated in terms of binding activity and moreover improved the, oral absorption (6a and 6b). Finally, transformation of indol-1-yl to, indol-3-yl resulted in discovery of a novel highly potent and orally, bioavailable ADA inhibitor, 1-[(R)-4-(5-(3-(4-chlorophenyl)propoxy)-1-methylindol-3-yl)-1-hydroxy-2-bu, tyl]imidazole-4-carboxamide 8c.
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<StructureSection load='1qxl' size='340' side='right'caption='[[1qxl]], [[Resolution|resolution]] 2.25&Aring;' scene=''>
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== Structural highlights ==
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<table><tr><td colspan='2'>[[1qxl]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Bos_taurus Bos taurus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1QXL OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1QXL 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]] 2.25&#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=FR8:1-((1R)-1-(HYDROXYMETHYL)-3-{6-[(5-PHENYLPENTANOYL)AMINO]-1H-INDOL-1-YL}PROPYL)-1H-IMIDAZOLE-4-CARBOXAMIDE'>FR8</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=1qxl FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1qxl OCA], [https://pdbe.org/1qxl PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1qxl RCSB], [https://www.ebi.ac.uk/pdbsum/1qxl PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1qxl ProSAT]</span></td></tr>
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</table>
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== Function ==
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[https://www.uniprot.org/uniprot/ADA_BOVIN ADA_BOVIN] Catalyzes the hydrolytic deamination of adenosine and 2-deoxyadenosine. Plays an important role in purine metabolism and in adenosine homeostasis. Modulates signaling by extracellular adenosine, and so contributes indirectly to cellular signaling events. Acts as a positive regulator of T-cell coactivation, by binding DPP4. Its interaction with DPP4 regulates lymphocyte-epithelial cell adhesion (By similarity).
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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/qx/1qxl_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=1qxl ConSurf].
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<div style="clear:both"></div>
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==About this Structure==
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==See Also==
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1QXL is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Bos_taurus Bos taurus] with ZN and FR8 as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Adenosine_deaminase Adenosine deaminase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.5.4.4 3.5.4.4] Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=1QXL OCA].
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*[[Adenosine deaminase 3D structures|Adenosine deaminase 3D structures]]
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__TOC__
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==Reference==
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</StructureSection>
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Structure-based design, synthesis, and structure-activity relationship studies of novel non-nucleoside adenosine deaminase inhibitors., Terasaka T, Kinoshita T, Kuno M, Seki N, Tanaka K, Nakanishi I, J Med Chem. 2004 Jul 15;47(15):3730-43. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=15239652 15239652]
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[[Category: Adenosine deaminase]]
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[[Category: Bos taurus]]
[[Category: Bos taurus]]
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[[Category: Single protein]]
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[[Category: Large Structures]]
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[[Category: Kinoshita, T.]]
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[[Category: Kinoshita T]]
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[[Category: FR8]]
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[[Category: ZN]]
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[[Category: beta barrel]]
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[[Category: zinc ion]]
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''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Wed Nov 21 01:05:45 2007''
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Current revision

Crystal structure of Adenosine deaminase complexed with FR235380

PDB ID 1qxl

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