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1pw6

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{{STRUCTURE_1pw6| PDB=1pw6 | SCENE= }}
{{STRUCTURE_1pw6| PDB=1pw6 | SCENE= }}
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'''Low Micromolar Small Molecule Inhibitor of IL-2'''
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===Low Micromolar Small Molecule Inhibitor of IL-2===
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==Overview==
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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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(as it appears on PubMed at http://www.pubmed.gov), where 14664558 is the PubMed ID number.
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{{ABSTRACT_PUBMED_14664558}}
==Disease==
==Disease==
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[[Category: Wells, J A.]]
[[Category: Wells, J A.]]
[[Category: Il-2 interleukin 2 small molecule inhibitor]]
[[Category: Il-2 interleukin 2 small molecule inhibitor]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sat May 3 05:33:25 2008''
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Tue Jul 29 14:27:34 2008''

Revision as of 11:27, 29 July 2008

Image:1pw6.png

Template:STRUCTURE 1pw6

Contents

Low Micromolar Small Molecule Inhibitor of IL-2

Template:ABSTRACT PUBMED 14664558

Disease

Known disease associated with this structure: Severe combined immunodeficiency due to IL2 deficiency OMIM:[147680]

About this Structure

1PW6 is a Single protein structure of sequence from Homo sapiens. 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 Tue Jul 29 14:27:34 2008

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