3O2M: Crystal Structure Of Jnk1-Alpha1 Isoform Complex With A Biaryl Tetrazol (A-82118)

Citation:
Abstract
Inhibition of protein kinases has validated therapeutic utility for cancer, with at least seven kinase inhibitor drugs on the market. Protein kinase inhibition also has significant potential for a variety of other diseases, including diabetes, pain, cognition, and chronic inflammatory and immunologic diseases. However, as the vast majority of current approaches to kinase inhibition target the highly conserved ATP-binding site, the use of kinase inhibitors in treating nononcology diseases may require great selectivity for the target kinase. As protein kinases are signal transducers that are involved in binding to a variety of other proteins, targeting alternative, less conserved sites on the protein may provide an avenue for greater selectivity. Here we report an affinity-based, high-throughput screening technique that allows nonbiased interrogation of small molecule libraries for binding to all exposed sites on a protein surface. This approach was used to screen both the c-Jun N-terminal protein kinase Jnk-1 (involved in insulin signaling) and p38alpha (involved in the formation of TNFalpha and other cytokines). In addition to canonical ATP-site ligands, compounds were identified that bind to novel allosteric sites. The nature, biological relevance, and mode of binding of these ligands were extensively characterized using two-dimensional (1)H/(13)C NMR spectroscopy, protein X-ray crystallography, surface plasmon resonance, and direct enzymatic activity and activation cascade assays. Jnk-1 and p38alpha both belong to the MAP kinase family, and the allosteric ligands for both targets bind similarly on a ledge of the protein surface exposed by the MAP insertion present in the CMGC family of protein kinases and distant from the active site. Medicinal chemistry studies resulted in an improved Jnk-1 ligand able to increase adiponectin secretion in human adipocytes and increase insulin-induced protein kinase PKB phosphorylation in human hepatocytes, in similar fashion to Jnk-1 siRNA and to rosiglitazone treatment. Together, the data suggest that these new ligand series bind to a novel, allosteric, and physiologically relevant site and therefore represent a unique approach to identify kinase inhibitors.
PDB ID: 3O2MDownload
MMDB ID: 87856
PDB Deposition Date: 2010/7/22
Updated in MMDB: 2011/09
Experimental Method:
x-ray diffraction
Resolution: 2.7  Å
Source Organism:
Mus musculus
Similar Structures:
Biological Unit for 3O2M: dimeric; determined by author and by software (PISA)
Molecular Components in 3O2M
Label Count Molecule
Proteins (2 molecules)
1
Mitogen-activated Protein Kinase 8(Gene symbol: MAPK8)
Molecule annotation
1
C-jun-amino-terminal Kinase-interacting Protein 1, Jip1, 10mer Peptide(Gene symbol: Mapk8ip1)
Molecule annotation
Chemicals (5 molecules)
1
2
2
3
* Click molecule labels to explore molecular sequence information.

Citing MMDB
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