1PY2

Structure of a 60 nM Small Molecule Bound to a Hot Spot on IL-2

Summary for 1PY2

• Entry DOI: 10.2210/pdb1py2/pdb
• Descriptor: Interleukin-2, 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, ZINC ION (3 entities in total)
• Functional Keywords: il-2, interleukin 2, small molecule, hot spot, molecular recognition, immune system
• Biological source: Homo sapiens (human)
• Cellular location: Secreted: P60568
• Total number of polymer chains: 4
• Total formula weight: 64185.99

Authors

Thanos, C.D.,Randal, M.,Wells, J.A. (deposition date: 2003-07-07, release date: 2004-01-13, Last modification date: 2024-10-30)

Primary citation

Thanos, C.D.,Randal, M.,Wells, J.A.
Potent small-molecule binding to a dynamic hot spot on IL-2.
J.Am.Chem.Soc., 125:15280-15281, 2003

PubMed Abstract: 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.

PubMed: 14664558
DOI: 10.1021/ja0382617

Experimental method

X-RAY DIFFRACTION (2.8 Å)