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Crystal structures of apo and inhibitor-bound TGFβR2 kinase domain: insights into TGFβR isoform selectivity.

Tebben AJ, Ruzanov M, Gao M, Xie D, Kiefer SE, Yan C, Newitt JA, Zhang L, Kim K, Lu H, Kopcho LM, Sheriff S
Acta Crystallogr D Struct Biol 72 658-74 (2016)
Related entries: 5e8s, 5e8t, 5e8u, 5e8v, 5e8w, 5e8x, 5e8y, 5e8z, 5e91, 5e92

Cited: 14 times
EuropePMC logo PMID: 27139629

Abstract

The cytokine TGF-β modulates a number of cellular activities and plays a critical role in development, hemostasis and physiology, as well as in diseases including cancer and fibrosis. TGF-β signals through two transmembrane serine/threonine kinase receptors: TGFβR1 and TGFβR2. Multiple structures of the TGFβR1 kinase domain are known, but the structure of TGFβR2 remains unreported. Wild-type TGFβR2 kinase domain was refractory to crystallization, leading to the design of two mutated constructs: firstly, a TGFβR1 chimeric protein with seven ATP-site residues mutated to their counterparts in TGFβR2, and secondly, a reduction of surface entropy through mutation of six charged residues on the surface of the TGFβR2 kinase domain to alanines. These yielded apo and inhibitor-bound crystals that diffracted to high resolution (<2 Å). Comparison of these structures with those of TGFβR1 reveal shared ligand contacts as well as differences in the ATP-binding sites, suggesting strategies for the design of pan and selective TGFβR inhibitors.

Reviews citing this publication (2)

  1. Structural basis for the potent and selective binding of LDN-212854 to the BMP receptor kinase ALK2. Williams E, Bullock AN. Bone 109 251-258 (2018)
  2. Structural biology of the TGFβ family. Goebel EJ, Hart KN, McCoy JC, Thompson TB. Exp Biol Med (Maywood) 244 1530-1546 (2019)

Articles citing this publication (12)

  1. Docking-based virtual screening of TβR1 inhibitors: evaluation of pose prediction and scoring functions. Wang S, Jiang JH, Li RY, Deng P. BMC Chem 14 52 (2020)
  2. Understanding the impacts of missense mutations on structures and functions of human cancer-related genes: A preliminary computational analysis of the COSMIC Cancer Gene Census. Malhotra S, Alsulami AF, Heiyun Y, Ochoa BM, Jubb H, Forbes S, Blundell TL. PLoS One 14 e0219935 (2019)
  3. Novel Transforming Growth Factor-Beta Receptor 1 Antagonists through a Pharmacophore-Based Virtual Screening Approach. Jiang J, Zhou H, Jiang Q, Sun L, Deng P. Molecules 23 E2824 (2018)
  4. TransDTI: Transformer-Based Language Models for Estimating DTIs and Building a Drug Recommendation Workflow. Kalakoti Y, Yadav S, Sundar D. ACS Omega 7 2706-2717 (2022)
  5. Discovery of 4-Azaindole Inhibitors of TGFβRI as Immuno-oncology Agents. Zhang Y, Zhao Y, Tebben AJ, Sheriff S, Ruzanov M, Fereshteh MP, Fan Y, Lippy J, Swanson J, Ho CP, Wautlet BS, Rose A, Parrish K, Yang Z, Donnell AF, Zhang L, Fink BE, Vite GD, Augustine-Rauch K, Fargnoli J, Borzilleri RM. ACS Med Chem Lett 9 1117-1122 (2018)
  6. "Let my liver rather heat with wine" - a review of hepatic fibrosis pathophysiology and emerging therapeutics. Moscoso CG, Steer CJ. Hepat Med 11 109-129 (2019)
  7. Silibinin Overcomes EMT-Driven Lung Cancer Resistance to New-Generation ALK Inhibitors. Verdura S, Encinar JA, Teixidor E, Segura-Carretero A, Micol V, Cuyàs E, Bosch-Barrera J, Menendez JA. Cancers (Basel) 14 6101 (2022)
  8. Synthesis and Evaluation of Novel 1,2,6-Thiadiazinone Kinase Inhibitors as Potent Inhibitors of Solid Tumors. Kalogirou AS, East MP, Laitinen T, Torrice CD, Maffuid KA, Drewry DH, Koutentis PA, Johnson GL, Crona DJ, Asquith CRM. Molecules 26 5911 (2021)
  9. Novel Sulforaphane Analog Disrupts Phosphatidylinositol-3-Kinase-Protein Kinase B Pathway and Inhibits Cancer Cell Progression via Reactive Oxygen Species-Mediated Caspase-Independent Apoptosis. Dutta A, Halder S, Bhaumik I, Debnath U, Dhara D, Misra AK, Jana K. ACS Pharmacol Transl Sci 7 195-211 (2024)
  10. Ovatodiolide inhibits SARS-CoV-2 replication and ameliorates pulmonary fibrosis through suppression of the TGF-β/TβRs signaling pathway. Chiou WC, Huang GJ, Chang TY, Hsia TL, Yu HY, Lo JM, Fu PK, Huang C. Biomed Pharmacother 161 114481 (2023)
  11. Synergistic effect of siRNA-mediated silencing of TGF-β R1 and TGF-β R2 genes on the proliferation and apoptosis of penile urethral epithelial cells in hypospadiac male rats. Wang C, Qiao YY. J Cell Biochem 119 1646-1658 (2018)
  12. Wound Healing Potential and In Silico Appraisal of Convolvulus arvensis L. Methanolic Extract. Saleem U, Khalid S, Zaib S, Anwar F, Akhtar MF, Hussain L, Saleem A, Ahmad B. Biomed Res Int 2022 1373160 (2022)


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