1QVN

Structure of SP4160 Bound to IL-2 V69A

Summary for 1QVN

• Entry DOI: 10.2210/pdb1qvn/pdb
• Descriptor: Interleukin-2, ZINC ION, 2-GUANIDINO-4-METHYL-PENTANOIC ACID [2-(4-{5-[4-(4-ACETYLAMINO-BENZYLOXY)-2,3-DICHLORO-PHENYL]-2-METHYL-2H-PYRAZOL-3-YL}-PIPERIDIN-1-YL)-2-OXO-ETHYL]-AMIDE (3 entities in total)
• Functional Keywords: il-2 small molecule hot spot, cytokine
• Biological source: Homo sapiens (human)
• Cellular location: Secreted: P60568
• Total number of polymer chains: 4
• Total formula weight: 64231.50

Authors

Thanos, C.D.,Delano, W.L.,Wells, J.A. (deposition date: 2003-08-28, release date: 2005-04-05, Last modification date: 2024-10-16)

Primary citation

Thanos, C.D.,DeLano, W.L.,Wells, J.A.
Hot-spot mimicry of a cytokine receptor by a small molecule.
Proc.Natl.Acad.Sci.USA, 103:15422-15427, 2006

PubMed Abstract: Protein-protein complexes remain enticing, but extremely challenging, targets for small-molecule drug discovery. In a rare example described earlier, a high-affinity small molecule, SP4206 (Kd approximately 70 nM), was found to block binding of the IL-2alpha receptor (IL-2Ralpha) to IL-2 (Kd approximately 10 nM). Recently, the structure of the IL-2/IL-2Ralpha complex was solved [Rickert, M., Wang, X., Boulanger, M. J., Goriatcheva, N., Garcia, K. C. (2005) Science 308:1477-1480]. Using structural and functional analysis, we compare how SP4206 mimics the 83-fold larger IL-2Ralpha in binding IL-2. The binding free energy per contact atom (ligand efficiency) for SP4206 is about twice that of the receptor because of a smaller, but overlapping, contact epitope that insinuates into grooves and cavities not accessed by the receptor. Despite its independent design, the small molecule has a similar, but more localized, charge distribution compared with IL-2Ralpha. Mutational studies show that SP4206 targets virtually the same critical "hot-spot" residues on IL-2 that drive binding of IL-2Ralpha. Moreover, a mutation that enhances binding to the IL-2Ralpha near these hot spots also enhances binding to SP4206. Although the protein and small molecule do bind the same hot spot, they trap very different conformations of IL-2 because of its flexible nature. Our studies suggest that precise structural mimics of receptors are not required for high-affinity binding of small molecules, and they show that there are multiple solutions to tight binding at shared and adaptive hot spots.

PubMed: 17032757
DOI: 10.1073/pnas.0607058103

Experimental method

X-RAY DIFFRACTION (2.7 Å)