1py2: Difference between revisions
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==Structure of a 60 nM Small Molecule Bound to a Hot Spot on IL-2== | ==Structure of a 60 nM Small Molecule Bound to a Hot Spot on IL-2== | ||
<StructureSection load='1py2' size='340' side='right' caption='[[1py2]], [[Resolution|resolution]] 2.80Å' scene=''> | <StructureSection load='1py2' size='340' side='right'caption='[[1py2]], [[Resolution|resolution]] 2.80Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[1py2]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1PY2 OCA]. For a <b>guided tour on the structure components</b> use [http:// | <table><tr><td colspan='2'>[[1py2]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1PY2 OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=1PY2 FirstGlance]. <br> | ||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=FRH:5-[2,3-DICHLORO-4-(5-{1-[2-(2-GUANIDINO-4-METHYL-PENTANOYLAMINO)-ACETYL]-PIPERIDIN-4-YL}-1-METHYL-1H-PYRAZOL-3-YL)-PHENOXYMETHYL]-FURAN-2-CARBOXYLIC+ACID'>FRH</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr> | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=FRH:5-[2,3-DICHLORO-4-(5-{1-[2-(2-GUANIDINO-4-METHYL-PENTANOYLAMINO)-ACETYL]-PIPERIDIN-4-YL}-1-METHYL-1H-PYRAZOL-3-YL)-PHENOXYMETHYL]-FURAN-2-CARBOXYLIC+ACID'>FRH</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr> | ||
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">IL2 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr> | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">IL2 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr> | ||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http:// | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=1py2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1py2 OCA], [http://pdbe.org/1py2 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=1py2 RCSB], [http://www.ebi.ac.uk/pdbsum/1py2 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=1py2 ProSAT]</span></td></tr> | ||
</table> | </table> | ||
== Disease == | == Disease == | ||
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==See Also== | ==See Also== | ||
*[[Interleukin|Interleukin]] | *[[Interleukin 3D structures|Interleukin 3D structures]] | ||
== References == | == References == | ||
<references/> | <references/> | ||
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</StructureSection> | </StructureSection> | ||
[[Category: Human]] | [[Category: Human]] | ||
[[Category: Large Structures]] | |||
[[Category: Randal, M]] | [[Category: Randal, M]] | ||
[[Category: Thanos, C D]] | [[Category: Thanos, C D]] | ||
Revision as of 10:38, 9 December 2020
Structure of a 60 nM Small Molecule Bound to a Hot Spot on IL-2Structure of a 60 nM Small Molecule Bound to a Hot Spot on IL-2
Structural highlights
Disease[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. Function[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. 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 PubMedThe 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. 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:14664558[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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