1py2
From Proteopedia
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==Overview== | ==Overview== | ||
| - | 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 | + | 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. |
==Disease== | ==Disease== | ||
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[[Category: Single protein]] | [[Category: Single protein]] | ||
[[Category: Randal, M.]] | [[Category: Randal, M.]] | ||
| - | [[Category: Thanos, C | + | [[Category: Thanos, C D.]] |
| - | [[Category: Wells, J | + | [[Category: Wells, J A.]] |
[[Category: FRH]] | [[Category: FRH]] | ||
[[Category: ZN]] | [[Category: ZN]] | ||
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[[Category: small molecule]] | [[Category: small molecule]] | ||
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 14:33:45 2008'' |
Revision as of 12:33, 21 February 2008
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Structure of a 60 nM Small Molecule Bound to a Hot Spot on IL-2
Contents |
Overview
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.
Disease
Known disease associated with this structure: Severe combined immunodeficiency due to IL2 deficiency OMIM:[147680]
About this Structure
1PY2 is a Single protein structure of sequence from Homo sapiens with and as ligands. Full crystallographic information is available from OCA.
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:14664558
Page seeded by OCA on Thu Feb 21 14:33:45 2008
Categories: Homo sapiens | Single protein | Randal, M. | Thanos, C D. | Wells, J A. | FRH | ZN | Hot spot | Il-2 | Interleukin 2 | Molecular recognition | Small molecule
