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1pw6

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[[Image:1pw6.gif|left|200px]]
 
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{{Structure
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==Low Micromolar Small Molecule Inhibitor of IL-2==
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|PDB= 1pw6 |SIZE=350|CAPTION= <scene name='initialview01'>1pw6</scene>, resolution 2.60&Aring;
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<StructureSection load='1pw6' size='340' side='right'caption='[[1pw6]], [[Resolution|resolution]] 2.60&Aring;' scene=''>
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|SITE=
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== Structural highlights ==
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|LIGAND= <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene> and <scene name='pdbligand=FRB:2-CYCLOHEXYL-N-(2-{4-[5-(2,3-DICHLORO-PHENYL)-2H-PYRAZOL-3-YL]-PIPERIDIN-1-YL}-2-OXO-ETHYL)-2-GUANIDINO-ACETAMIDE'>FRB</scene>
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<table><tr><td colspan='2'>[[1pw6]] 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=1PW6 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1PW6 FirstGlance]. <br>
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|ACTIVITY=
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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]] 2.6&#8491;</td></tr>
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|GENE= IL2 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens])
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=FRB:2-CYCLOHEXYL-N-(2-{4-[5-(2,3-DICHLORO-PHENYL)-2H-PYRAZOL-3-YL]-PIPERIDIN-1-YL}-2-OXO-ETHYL)-2-GUANIDINO-ACETAMIDE'>FRB</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
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}}
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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=1pw6 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1pw6 OCA], [https://pdbe.org/1pw6 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1pw6 RCSB], [https://www.ebi.ac.uk/pdbsum/1pw6 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1pw6 ProSAT]</span></td></tr>
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</table>
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== Disease ==
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[https://www.uniprot.org/uniprot/IL2_HUMAN IL2_HUMAN] Note=A chromosomal aberration involving IL2 is found in a form of T-cell acute lymphoblastic leukemia (T-ALL). Translocation t(4;16)(q26;p13) with involves TNFRSF17.
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== Function ==
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[https://www.uniprot.org/uniprot/IL2_HUMAN IL2_HUMAN] Produced by T-cells in response to antigenic or mitogenic stimulation, this protein is required for T-cell proliferation and other activities crucial to regulation of the immune response. Can stimulate B-cells, monocytes, lymphokine-activated killer cells, natural killer cells, and glioma cells.
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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/pw/1pw6_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=1pw6 ConSurf].
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<div style="clear:both"></div>
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'''Low Micromolar Small Molecule Inhibitor of IL-2'''
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==See Also==
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*[[Interleukin 3D structures|Interleukin 3D structures]]
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__TOC__
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==Overview==
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</StructureSection>
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The complexes between IL-2 and two similar small molecules, one a lead compound and the other a potent, affinity-optimized compound, were determined by X-ray crystallography. The lead compound (IC50 = 6 muM) bound to a hot spot on IL-2 in a groove that is not apparent in either the unliganded protein or a complex between IL-2 and a weakly bound drug fragment. The affinity-optimized compound (IC50 = 0.06 muM), which has an added aromatic acid fragment, bound in the same groove as the lead compound. In addition, a novel binding site was formed for the aromatic acid which is unseen in the complex with the lead compound. Thus, the hot spot on IL-2 is highly dynamic, with the protein changing form at multiple sites to maximize packing for each compound. Binding-site rigidity is often thought to play a role in high-affinity interactions. However, in this case, specific contacts between the small molecule and the protein are made despite the adaptivity of the hot spot. Given the change in morphology that was observed in IL-2, it is unlikely that a potent inhibitor could have been found by rational design. Therefore, fragment assembly methods offer the stochastic advantage of finding fragments in flexible protein regions where structural changes are unpredictable.
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==Disease==
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Known disease associated with this structure: Severe combined immunodeficiency due to IL2 deficiency OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=147680 147680]]
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==About this Structure==
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1PW6 is a [[Single protein]] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1PW6 OCA].
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==Reference==
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Potent small-molecule binding to a dynamic hot spot on IL-2., Thanos CD, Randal M, Wells JA, J Am Chem Soc. 2003 Dec 17;125(50):15280-1. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/14664558 14664558]
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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: Randal, M.]]
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[[Category: Randal M]]
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[[Category: Thanos, C D.]]
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[[Category: Thanos CD]]
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[[Category: Wells, J A.]]
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[[Category: Wells JA]]
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[[Category: FRB]]
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[[Category: SO4]]
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[[Category: il-2 interleukin 2 small molecule inhibitor]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Mar 20 13:29:43 2008''
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Current revision

Low Micromolar Small Molecule Inhibitor of IL-2

PDB ID 1pw6

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