1py2: Difference between revisions
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'''Structure of a 60 nM Small Molecule Bound to a Hot Spot on IL-2''' | {{Structure | ||
|PDB= 1py2 |SIZE=350|CAPTION= <scene name='initialview01'>1py2</scene>, resolution 2.80Å | |||
|SITE= | |||
|LIGAND= <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene> and <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> | |||
|ACTIVITY= | |||
|GENE= IL2 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens]) | |||
}} | |||
'''Structure of a 60 nM Small Molecule Bound to a Hot Spot on IL-2''' | |||
==Overview== | ==Overview== | ||
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==About this Structure== | ==About this Structure== | ||
1PY2 is a [ | 1PY2 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=1PY2 OCA]. | ||
==Reference== | ==Reference== | ||
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:// | 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] | ||
[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
[[Category: Single protein]] | [[Category: Single protein]] | ||
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[[Category: small molecule]] | [[Category: small molecule]] | ||
''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Mar 20 13:30:30 2008'' | ||
Revision as of 14:30, 20 March 2008
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| , resolution 2.80Å | |||||||
|---|---|---|---|---|---|---|---|
| Ligands: | and | ||||||
| Gene: | IL2 (Homo sapiens) | ||||||
| Coordinates: | save as pdb, mmCIF, xml | ||||||
Structure of a 60 nM Small Molecule Bound to a Hot Spot on IL-2
OverviewOverview
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.
DiseaseDisease
Known disease associated with this structure: Severe combined immunodeficiency due to IL2 deficiency OMIM:[147680]
About this StructureAbout this Structure
1PY2 is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.
ReferenceReference
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
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