5KML

TrkA JM-kinase with 1-(5-methyl-3-phenyl-1,2-oxazol-4-yl)-3-[[2-(trifluoromethyl)phenyl]methyl]urea

Summary for 5KML

• Entry DOI: 10.2210/pdb5kml/pdb
• Related: 5KMI 5KMJ 5KMK 5KMM 5KMN 5KMO
• Descriptor: High affinity nerve growth factor receptor, 1-(5-methyl-3-phenyl-1,2-oxazol-4-yl)-3-[[2-(trifluoromethyl)phenyl]methyl]urea (3 entities in total)
• Functional Keywords: kinase, juxtamembrane, inhibitor, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (Human)
• Cellular location: Cell membrane ; Single-pass type I membrane protein : P04629
• Total number of polymer chains: 1
• Total formula weight: 37668.13

Authors

Su, H.P. (deposition date: 2016-06-27, release date: 2016-12-28, Last modification date: 2024-10-16)

Primary citation

Su, H.P.,Rickert, K.,Burlein, C.,Narayan, K.,Bukhtiyarova, M.,Hurzy, D.M.,Stump, C.A.,Zhang, X.,Reid, J.,Krasowska-Zoladek, A.,Tummala, S.,Shipman, J.M.,Kornienko, M.,Lemaire, P.A.,Krosky, D.,Heller, A.,Achab, A.,Chamberlin, C.,Saradjian, P.,Sauvagnat, B.,Yang, X.,Ziebell, M.R.,Nickbarg, E.,Sanders, J.M.,Bilodeau, M.T.,Carroll, S.S.,Lumb, K.J.,Soisson, S.M.,Henze, D.A.,Cooke, A.J.
Structural characterization of nonactive site, TrkA-selective kinase inhibitors.
Proc. Natl. Acad. Sci. U.S.A., 114:E297-E306, 2017

PubMed Abstract: Current therapies for chronic pain can have insufficient efficacy and lead to side effects, necessitating research of novel targets against pain. Although originally identified as an oncogene, Tropomyosin-related kinase A (TrkA) is linked to pain and elevated levels of NGF (the ligand for TrkA) are associated with chronic pain. Antibodies that block TrkA interaction with its ligand, NGF, are in clinical trials for pain relief. Here, we describe the identification of TrkA-specific inhibitors and the structural basis for their selectivity over other Trk family kinases. The X-ray structures reveal a binding site outside the kinase active site that uses residues from the kinase domain and the juxtamembrane region. Three modes of binding with the juxtamembrane region are characterized through a series of ligand-bound complexes. The structures indicate a critical pharmacophore on the compounds that leads to the distinct binding modes. The mode of interaction can allow TrkA selectivity over TrkB and TrkC or promiscuous, pan-Trk inhibition. This finding highlights the difficulty in characterizing the structure-activity relationship of a chemical series in the absence of structural information because of substantial differences in the interacting residues. These structures illustrate the flexibility of binding to sequences outside of-but adjacent to-the kinase domain of TrkA. This knowledge allows development of compounds with specificity for TrkA or the family of Trk proteins.

PubMed: 28039433
DOI: 10.1073/pnas.1611577114

Experimental method

X-RAY DIFFRACTION (2.01 Å)