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Structural insights into the inhibited states of the Mer receptor tyrosine kinase.

Huang X, Finerty P, Walker JR, Butler-Cole C, Vedadi M, Schapira M, Parker SA, Turk BE, Thompson DA, Dhe-Paganon S
J Struct Biol 165 88-96 (2009)
Related entries: 2p0c, 3brb

Cited: 32 times
EuropePMC logo PMID: 19028587

Abstract

The mammalian ortholog of the retroviral oncogene v-Eyk, and a receptor tyrosine kinase upstream of antiapoptotic and transforming signals, Mer (MerTK) is a mediator of the phagocytic process, being involved in retinal and immune cell clearance and platelet aggregation. Mer knockout mice are viable and are protected from epinephrine-induced pulmonary thromboembolism and ferric chloride-induced thrombosis. Mer overexpression, on the other hand, is associated with numerous carcinomas. Although Mer adaptor proteins and signaling pathways have been identified, it remains unclear how Mer initiates phagocytosis. When bound to its nucleotide cofactor, the high-resolution structure of Mer shows an autoinhibited alphaC-Glu-out conformation with insertion of an activation loop residue into the active site. Mer complexed with compound-52 (C52: 2-(2-hydroxyethylamino)-6-(3-chloroanilino)-9-isopropylpurine), a ligand identified from a focused library, retains its DFG-Asp-in and alphaC-Glu-out conformation, but acquires other conformational changes. The alphaC helix and DFGL region is closer to the hinge region and the ethanolamine moiety of C52 binds in the groove formed between Leu593 and Val601 of the P-loop, causing a compression of the active site pocket. These conformational states reveal the mechanisms of autoinhibition, the pathophysiological basis of disease-causing mutations, and a platform for the development of chemical probes.

Articles - 3bpr mentioned but not cited (4)

  1. Structural insights into the inhibited states of the Mer receptor tyrosine kinase. Huang X, Finerty P, Walker JR, Butler-Cole C, Vedadi M, Schapira M, Parker SA, Turk BE, Thompson DA, Dhe-Paganon S. J Struct Biol 165 88-96 (2009)
  2. Discovery of Mer kinase inhibitors by virtual screening using Structural Protein-Ligand Interaction Fingerprints. Da C, Stashko M, Jayakody C, Wang X, Janzen W, Frye S, Kireev D. Bioorg Med Chem 23 1096-1101 (2015)
  3. Structural elucidation of the DFG-Asp in and DFG-Asp out states of TAM kinases and insight into the selectivity of their inhibitors. Messoussi A, Peyronnet L, Feneyrolles C, Chevé G, Bougrin K, Yasri A. Molecules 19 16223-16239 (2014)
  4. A-loop interactions in Mer tyrosine kinase give rise to inhibitors with two-step mechanism and long residence time of binding. Pflug A, Schimpl M, Nissink JWM, Overman RC, Rawlins PB, Truman C, Underwood E, Warwicker J, Winter-Holt J, McCoull W. Biochem J 477 4443-4452 (2020)


Reviews citing this publication (8)

  1. Biology of the TAM receptors. Lemke G. Cold Spring Harb Perspect Biol 5 a009076 (2013)
  2. Taking aim at Mer and Axl receptor tyrosine kinases as novel therapeutic targets in solid tumors. Linger RM, Keating AK, Earp HS, Graham DK. Expert Opin Ther Targets 14 1073-1090 (2010)
  3. Molecular pathways: MERTK signaling in cancer. Cummings CT, Deryckere D, Earp HS, Graham DK. Clin Cancer Res 19 5275-5280 (2013)
  4. The Emerging Role of TYRO3 as a Therapeutic Target in Cancer. Smart SK, Vasileiadi E, Wang X, DeRyckere D, Graham DK. Cancers (Basel) 10 E474 (2018)
  5. MERTK in cancer therapy: Targeting the receptor tyrosine kinase in tumor cells and the immune system. Huelse JM, Fridlyand DM, Earp S, DeRyckere D, Graham DK. Pharmacol Ther 213 107577 (2020)
  6. New Insights into the Role of Tyro3, Axl, and Mer Receptors in Rheumatoid Arthritis. Pagani S, Bellan M, Mauro D, Castello LM, Avanzi GC, Lewis MJ, Sainaghi PP, Pitzalis C, Nerviani A. Dis Markers 2020 1614627 (2020)
  7. Drug discovery in academic institutions. Frye SV. Hematology Am Soc Hematol Educ Program 2013 300-305 (2013)
  8. Therapeutic targeting of the functionally elusive TAM receptor family. Miao YR, Rankin EB, Giaccia AJ. Nat Rev Drug Discov (2023)

Articles citing this publication (20)

  1. Differential TAM receptor-ligand-phospholipid interactions delimit differential TAM bioactivities. Lew ED, Oh J, Burrola PG, Lax I, Zagórska A, Través PG, Schlessinger J, Lemke G. Elife 3 (2014)
  2. UNC2025, a potent and orally bioavailable MER/FLT3 dual inhibitor. Zhang W, DeRyckere D, Hunter D, Liu J, Stashko MA, Minson KA, Cummings CT, Lee M, Glaros TG, Newton DL, Sather S, Zhang D, Kireev D, Janzen WP, Earp HS, Graham DK, Frye SV, Wang X. J Med Chem 57 7031-7041 (2014)
  3. Discovery of Novel Small Molecule Mer Kinase Inhibitors for the Treatment of Pediatric Acute Lymphoblastic Leukemia. Liu J, Yang C, Simpson C, Deryckere D, Van Deusen A, Miley MJ, Kireev D, Norris-Drouin J, Sather S, Hunter D, Korboukh VK, Patel HS, Janzen WP, Machius M, Johnson GL, Earp HS, Graham DK, Frye SV, Wang X. ACS Med Chem Lett 3 129-134 (2012)
  4. Identity-by-descent-guided mutation analysis and exome sequencing in consanguineous families reveals unusual clinical and molecular findings in retinal dystrophy. Coppieters F, Van Schil K, Bauwens M, Verdin H, De Jaegher A, Syx D, Sante T, Lefever S, Abdelmoula NB, Depasse F, Casteels I, de Ravel T, Meire F, Leroy BP, De Baere E. Genet Med 16 671-680 (2014)
  5. UNC1062, a new and potent Mer inhibitor. Liu J, Zhang W, Stashko MA, Deryckere D, Cummings CT, Hunter D, Yang C, Jayakody CN, Cheng N, Simpson C, Norris-Drouin J, Sather S, Kireev D, Janzen WP, Earp HS, Graham DK, Frye SV, Wang X. Eur J Med Chem 65 83-93 (2013)
  6. UNC569, a novel small-molecule mer inhibitor with efficacy against acute lymphoblastic leukemia in vitro and in vivo. Christoph S, Deryckere D, Schlegel J, Frazer JK, Batchelor LA, Trakhimets AY, Sather S, Hunter DM, Cummings CT, Liu J, Yang C, Kireev D, Simpson C, Norris-Drouin J, Hull-Ryde EA, Janzen WP, Johnson GL, Wang X, Frye SV, Earp HS, Graham DK. Mol Cancer Ther 12 2367-2377 (2013)
  7. Global analysis of human nonreceptor tyrosine kinase specificity using high-density peptide microarrays. Deng Y, Alicea-Velázquez NL, Bannwarth L, Lehtonen SI, Boggon TJ, Cheng HC, Hytönen VP, Turk BE. J Proteome Res 13 4339-4346 (2014)
  8. MERTK controls melanoma cell migration and survival and differentially regulates cell behavior relative to AXL. Tworkoski KA, Platt JT, Bacchiocchi A, Bosenberg M, Boggon TJ, Stern DF. Pigment Cell Melanoma Res 26 527-541 (2013)
  9. αC helix as a switch in the conformational transition of Src/CDK-like kinase domains. Huang H, Zhao R, Dickson BM, Skeel RD, Post CB. J Phys Chem B 116 4465-4475 (2012)
  10. MERTK interactions with SH2-domain proteins in the retinal pigment epithelium. Shelby SJ, Colwill K, Dhe-Paganon S, Pawson T, Thompson DA. PLoS One 8 e53964 (2013)
  11. TAM receptors in leukemia: expression, signaling, and therapeutic implications. Brandão L, Migdall-Wilson J, Eisenman K, Graham DK. Crit Rev Oncog 16 47-63 (2011)
  12. Defining the substrate specificity determinants recognized by the active site of C-terminal Src kinase-homologous kinase (CHK) and identification of β-synuclein as a potential CHK physiological substrate. Ia KK, Jeschke GR, Deng Y, Kamaruddin MA, Williamson NA, Scanlon DB, Culvenor JG, Hossain MI, Purcell AW, Liu S, Zhu HJ, Catimel B, Turk BE, Cheng HC. Biochemistry 50 6667-6677 (2011)
  13. The Axl kinase domain in complex with a macrocyclic inhibitor offers first structural insights into an active TAM receptor kinase. Gajiwala KS, Grodsky N, Bolaños B, Feng J, Ferre R, Timofeevski S, Xu M, Murray BW, Johnson TW, Stewart A. J Biol Chem 292 15705-15716 (2017)
  14. Development of Potent Inhibitors of Receptor Tyrosine Kinases by Ligand-Based Drug Design and Target-Biased Phenotypic Screening. Myers SH, Temps C, Houston DR, Brunton VG, Unciti-Broceta A. J Med Chem 61 2104-2110 (2018)
  15. Discovering novel 7-azaindole-based series as potent AXL kinase inhibitors. Feneyrolles C, Guiet L, Singer M, Van Hijfte N, Daydé-Cazals B, Fauvel B, Chevé G, Yasri A. Bioorg Med Chem Lett 27 862-866 (2017)
  16. A course-based undergraduate research experience in biochemistry that is suitable for students with various levels of preparedness. Shelby SJ. Biochem Mol Biol Educ 47 220-227 (2019)
  17. Crystal Structure of the Kinase Domain of MerTK in Complex with AZD7762 Provides Clues for Structure-Based Drug Development. Park TH, Bae SH, Bong SM, Ryu SE, Jang H, Lee BI. Int J Mol Sci 21 E7878 (2020)
  18. Promiscuity and selectivity of small-molecule inhibitors across TAM receptor tyrosine kinases in pediatric leukemia. Liu MH, Chen SB, Yu J, Liu CJ, Zhang XJ. J Mol Graph Model 75 125-131 (2017)
  19. Synthesis, biological evaluation, and physicochemical property assessment of 4-substituted 2-phenylaminoquinazolines as Mer tyrosine kinase inhibitors. Wang SB, Cui MT, Wang XF, Ohkoshi E, Goto M, Yang DX, Li L, Yuan S, Morris-Natschke SL, Lee KH, Xie L. Bioorg Med Chem 24 3083-3092 (2016)
  20. Targeted Phagocytosis Induction for Cancer Immunotherapy via Bispecific MerTK-Engaging Antibodies. Carrara SC, Bogen JP, Fiebig D, Grzeschik J, Hock B, Kolmar H. Int J Mol Sci 23 15673 (2022)


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