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The crystal structures of TrkA and TrkB suggest key regions for achieving selective inhibition.

Bertrand T, Kothe M, Liu J, Dupuy A, Rak A, Berne PF, Davis S, Gladysheva T, Valtre C, Crenne JY, Mathieu M
J Mol Biol 423 439-53 (2012)
Related entries: 4asz, 4at3, 4at5, 4f0i

Cited: 55 times
EuropePMC logo PMID: 22902478

Abstract

The Trk family of neurotrophin receptors, which includes the three highly homologous proteins TrkA, TrkB and TrkC, is strongly associated with central and peripheral nervous system processes. Trk proteins are also of interest in oncology, since Trk activation has been observed in several cancer types. While Trk kinases are attractive oncology targets, selectivity might be more of an issue than for other kinases due to potential CNS side effects if several Trk kinases are simultaneously targeted. In order to address this issue, we present here the first structures of human TrkA and TrkB kinase domains and three complexes between TrkB and Trk inhibitors. These structures reveal different conformations of the kinase domain and suggest new regions of selectivity among the Trk family.

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  4. Genomic subtyping and therapeutic targeting of acute erythroleukemia. Iacobucci I, Wen J, Meggendorfer M, Choi JK, Shi L, Pounds SB, Carmichael CL, Masih KE, Morris SM, Lindsley RC, Janke LJ, Alexander TB, Song G, Qu C, Li Y, Payne-Turner D, Tomizawa D, Kiyokawa N, Valentine M, Valentine V, Basso G, Locatelli F, Enemark EJ, Kham SKY, Yeoh AEJ, Ma X, Zhou X, Sioson E, Rusch M, Ries RE, Stieglitz E, Hunger SP, Wei AH, To LB, Lewis ID, D'Andrea RJ, Kile BT, Brown AL, Scott HS, Hahn CN, Marlton P, Pei D, Cheng C, Loh ML, Ebert BL, Meshinchi S, Haferlach T, Mullighan CG. Nat Genet 51 694-704 (2019)
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  12. Oral and craniofacial manifestations and two novel missense mutations of the NTRK1 gene identified in the patient with congenital insensitivity to pain with anhidrosis. Gao L, Guo H, Ye N, Bai Y, Liu X, Yu P, Xue Y, Ma S, Wei K, Jin Y, Wen L, Xuan K. PLoS One 8 e66863 (2013)
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  14. Human BDNF/TrkB variants impair hippocampal synaptogenesis and associate with neurobehavioural abnormalities. Sonoyama T, Stadler LKJ, Zhu M, Keogh JM, Henning E, Hisama F, Kirwan P, Jura M, Blaszczyk BK, DeWitt DC, Brouwers B, Hyvönen M, Barroso I, Merkle FT, Appleyard SM, Wayman GA, Farooqi IS. Sci Rep 10 9028 (2020)
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  18. Bisphosphonate-Linked TrkB Agonist: Cochlea-Targeted Delivery of a Neurotrophic Agent as a Strategy for the Treatment of Hearing Loss. Kempfle JS, Nguyen K, Hamadani C, Koen N, Edge AS, Kashemirov BA, Jung DH, McKenna CE. Bioconjug Chem 29 1240-1250 (2018)
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  20. Impairment of kindling development in phospholipase Cγ1 heterozygous mice. He XP, Wen R, McNamara JO. Epilepsia 55 456-463 (2014)
  21. Synthesis, anticancer, and docking studies of salicyl-hydrazone analogues: A novel series of small potent tropomyosin receptor kinase A inhibitors. Alam MS, Choi SU, Lee DU. Bioorg Med Chem 25 389-396 (2017)
  22. Computational analysis of data from a genome-wide screening identifies new PARP1 functional interactors as potential therapeutic targets. Lodovichi S, Mercatanti A, Cervelli T, Galli A. Oncotarget 10 2722-2737 (2019)
  23. The juxtamembrane region of TrkA kinase is critical for inhibitor selectivity. Furuya N, Momose T, Katsuno K, Fushimi N, Muranaka H, Handa C, Ozawa T, Kinoshita T. Bioorg Med Chem Lett 27 1233-1236 (2017)
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  26. Novel 5-substituted-2-anilinoquinolines with 3-(morpholino or 4-methylpiperazin-1-yl)propoxy moiety as broad spectrum antiproliferative agents: Synthesis, cell based assays and kinase screening. El-Damasy AK, Cho NC, Pae AN, Kim EE, Keum G. Bioorg Med Chem Lett 26 3307-3312 (2016)
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  29. HIT web server: A hybrid method to improve electrostatic calculations for biomolecules. Sun S, Lopez JA, Xie Y, Guo W, Liu D, Li L. Comput Struct Biotechnol J 20 1580-1583 (2022)
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  31. Extracellular Juxtamembrane Motif Critical for TrkB Preformed Dimer and Activation. Shen J, Sun D, Shao J, Chen Y, Pang K, Guo W, Lu B. Cells 8 E932 (2019)
  32. Comparison of tyrosine kinase domain properties for the neurotrophin receptors TrkA and TrkB. Artim SC, Kiyatkin A, Lemmon MA. Biochem J 477 4053-4070 (2020)
  33. NVL-520 Is a Selective, TRK-Sparing, and Brain-Penetrant Inhibitor of ROS1 Fusions and Secondary Resistance Mutations. Drilon A, Horan JC, Tangpeerachaikul A, Besse B, Ou SI, Gadgeel SM, Camidge DR, van der Wekken AJ, Nguyen-Phuong L, Acker A, Keddy C, Nicholson KS, Yoda S, Mente S, Sun Y, Soglia JR, Kohl NE, Porter JR, Shair MD, Zhu V, Davare MA, Hata AN, Pelish HE, Lin JJ. Cancer Discov 13 598-615 (2023)
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  35. Interaction between a Novel Oligopeptide Fragment of the Human Neurotrophin Receptor TrkB Ectodomain D5 and the C-Terminal Fragment of Tetanus Neurotoxin. Candalija A, Scior T, Rackwitz HR, Ruiz-Castelan JE, Martinez-Laguna Y, Aguilera J. Molecules 26 3988 (2021)
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