Structural basis for Smoothened receptor modulation and chemoresistance to anticancer drugs

Nature Communications

Volumn 5, Issue , 2014, Pages

  Wang, Chong ^a   Wu, Huixian ^a   Evron, Tama ^b   Vardy, Eyal ^c   Han, Gye Won ^a   Huang, Xi Ping ^c   Hufeisen, Sandy J ^c   Mangano, Thomas J ^c   Urban, Dan J ^c   Katritch, Vsevolod ^a   Cherezov, Vadim ^a   Caron, Marc G ^b   Roth, Bryan L ^c   Stevens, Raymond C ^a  

^a SCRIPPS RESEARCH INSTITUTE   (United States)

^b DUKE UNIVERSITY MEDICAL CENTER   (United States)

^c NATIONAL INSTITUTE OF MENTAL HEALTH   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

AMIDE; ANTINEOPLASTIC AGENT; CYCLOPAMINE; PIPERAZINE DERIVATIVE; PYRAZOLE DERIVATIVE; SMOOTHENED PROTEIN; SONIDEGIB; TALADEGIB; UNCLASSIFIED DRUG; VISMODEGIB; [2 [6 [4 (4 BENZYLPHTHALAZIN 1 YL)PIPERAZIN 1 YL]PYRIDIN 3 YL]PROPAN 2 OL]; [3 CHLORO 4,7 DIFLUORO N [TRANS 4 (METHYLAMINO)CYCLOHEXYL] N [[3 (4 PYRIDINYL)PHENYL]METHYL] 1 BENZOTHIOPHENE 2 CARBOXAMIDE]; [3 CHLORO N [4 (METHYLAMINO)CYCLOHEXYL] N [3 (PYRIDIN 4 YL)BENZYL]BENZO[B]THIOPHENE 2 CARBOXAMIDE]; [N [(1E) (3,5 DIMETHYL 1 PHENYL 1H PYRAZOL 4 YL)METHYLIDENE] 4 (PHENYLMETHYL) 1 PIPERAZINAMINE]; 2-N,N-BIS(CARBOXYMETHYL)LYSINE; CYCLOHEXYLAMINE DERIVATIVE; G PROTEIN COUPLED RECEPTOR; LYSINE; SAG COMPOUND; SANT-1 COMPOUND; SMO PROTEIN, HUMAN; SONIC HEDGEHOG PROTEIN; THIOPHENE DERIVATIVE;

CANCER; CRYSTAL STRUCTURE; DRUG; DRUG RESISTANCE; LIGAND; MUTATION; TUMOR;

ANIMAL CELL; ARTICLE; BINDING SITE; CHEMOREACTIVITY; CONFORMATIONAL TRANSITION; CONTROLLED STUDY; CRYSTAL STRUCTURE; GEL PERMEATION CHROMATOGRAPHY; GENE REARRANGEMENT; HUMAN; HYDROGEN BOND; INCUBATION TIME; INSECT CELL; LIGAND BINDING; MODULATION; MOLECULAR RECOGNITION; MUTAGENESIS; NONHUMAN; SIGNAL TRANSDUCTION; STRUCTURE ACTIVITY RELATION; ANALOGS AND DERIVATIVES; CHEMICAL STRUCTURE; CHEMISTRY; CRYSTALLOGRAPHY; DRUG EFFECTS; DRUG RESISTANCE; PHYSIOLOGY;

ANTINEOPLASTIC AGENTS; CRYSTALLOGRAPHY; CYCLOHEXYLAMINES; DRUG RESISTANCE, NEOPLASM; HEDGEHOG PROTEINS; HUMANS; LYSINE; MODELS, MOLECULAR; PIPERAZINES; PYRAZOLES; RECEPTORS, G-PROTEIN-COUPLED; SIGNAL TRANSDUCTION; THIOPHENES;

EID: 84904325982     PISSN: None     EISSN: 20411723     Source Type: Journal    
DOI: 10.1038/ncomms5355     Document Type: Article

References (56)

1. Ingham, P. W. & McMahon, A. P. Hedgehog signaling in animal development: paradigms and principles. Genes Dev. 15, 3059-3087 (2001). (Pubitemid 33115673)
2. Robbins, D. J., Fei, D. L. & Riobo, N. A. The Hedgehog signal transduction network. Sci. Signal. 5, re6 (2012).
3. Pasca di Magliano, M. & Hebrok, M. Hedgehog signalling in cancer formation and maintenance. Nat. Rev. Cancer 3, 903-911 (2003). (Pubitemid 37500175)
4. Taipale, J. et al. Effects of oncogenic mutations in Smoothened and Patched can be reversed by cyclopamine. Nature 406, 1005-1009 (2000).
5. Mahindroo, N., Punchihewa, C. & Fujii, N. Hedgehog-Gli signaling pathway inhibitors as anticancer agents. J. Med. Chem. 52, 3829-3845 (2009).
6. Chen, J. K., Taipale, J., Cooper, M. K. & Beachy, P. A. Inhibition of Hedgehog signaling by direct binding of cyclopamine to Smoothened. Genes Dev. 16, 2743-2748 (2002). (Pubitemid 35253140)
7. Robarge, K. D. et al. GDC-0449-a potent inhibitor of the hedgehog pathway. Bioorg. Med. Chem. Lett. 19, 5576-5581 (2009).
8. Von Hoff, D. D. et al. Inhibition of the hedgehog pathway in advanced basal-cell carcinoma. New Engl. J. Med. 361, 1164-1172 (2009).
9. Wang, C. et al. Structure of the human smoothened receptor bound to an antitumour agent. Nature 497, 338-343 (2013).
10. Ballesteros, J. A. & Weinstein, H. Integrated methods for the construction of three dimensional models and computational probing of structure-function relations in G-protein coupled receptors. Methods Neurosci. 25, 366-428 (1995).
11. Yauch, R. L. et al. Smoothened mutation confers resistance to a Hedgehog pathway inhibitor in medulloblastoma. Science 326, 572-574 (2009).
12. Dijkgraaf, G. J. et al. Small molecule inhibition of GDC-0449 refractory smoothened mutants and downstream mechanisms of drug resistance. Cancer Res. 71, 435-444 (2011).
13. Tao, H. et al. Small molecule antagonists in distinct binding modes inhibit drug-resistant mutant of smoothened. Chem. Biol. 18, 432-437 (2011).
14. Peukert, S. et al. Discovery of NVP-LEQ506, a second-generation inhibitor of smoothened. ChemMedChem 8, 1261-1265 (2013).
15. Chen, J. K., Taipale, J., Young, K. E., Maiti, T. & Beachy, P. A. Small molecule modulation of Smoothened activity. Proc. Natl Acad. Sci. USA 99, 14071-14076 (2002). (Pubitemid 35257626)
16. Frank-Kamenetsky, M. et al. Small-molecule modulators of Hedgehog signaling: identification and characterization of Smoothened agonists and antagonists. J. Biol. 1, 10 (2002).
17. Rohatgi, R., Milenkovic, L., Corcoran, R. B. & Scott, M. P. Hedgehog signal transduction by Smoothened: pharmacologic evidence for a 2-step activation process. Proc. Natl Acad. Sci. USA 106, 3196-3201 (2009).
18. Teperino, R. et al. Hedgehog partial agonism drives Warburg-like metabolism in muscle and brown fat. Cell 151, 414-426 (2012).
19. Miller-Moslin, K. et al. 1-amino-4-benzylphthalazines as orally bioavailable smoothened antagonists with antitumor activity. J. Med. Chem. 52, 3954-3968 (2009).
20. Weierstall, U. et al. Lipidic cubic phase injector facilitates membrane protein serial femtosecond crystallography. Nat. Commun. 5, 3309 (2014).
21. Rominger, C. M. et al. Evidence for allosteric interactions of antagonist binding to the smoothened receptor. J. Pharmacol. Exp. Ther. 329, 995-1005 (2009).
22. Beachy, P. A. Regulators of the Hedgehog Pathway, Compostitions and Uses Related Thereto. European Patent no. 1235851 A2 (2001).
23. Carballeira, L. & Perez-Juste, I. Influence of calculation level and effect of methylation on axial/equatorial equilibria in piperidines. J. Comput. Chem. 19, 961-976 (1998). (Pubitemid 128611147)
24. Bender, M. H. et al. Abstract 2819: Identification and characterization of a novel smoothened antagonist for the treatment of cancer with deregulated hedgehog signaling. Cancer Res. 71, A2819 (2011).
25. Yang, H. et al. Converse conformational control of smoothened activity by structurally related small molecules. J. Biol. Chem. 284, 20876-20884 (2009).
26. Myers, B. R. et al. Hedgehog pathway modulation by multiple lipid binding sites on the smoothened effector of signal response. Dev. Cell 26, 346-357 (2013).
27. Nachtergaele, S. et al. Structure and function of the Smoothened extracellular domain in vertebrate Hedgehog signaling. Elife 2, e01340 (2013).
28. Nedelcu, D., Liu, J., Xu, Y., Jao, C. & Salic, A. Oxysterol binding to the extracellular domain of Smoothened in Hedgehog signaling. Nat. Chem. Biol. 9, 557-564 (2013).
29. Xie, J. et al. Activating Smoothened mutations in sporadic basal-cell carcinoma. Nature 391, 90-92 (1998). (Pubitemid 28079221)
30. Corbit, K. C. et al. Vertebrate Smoothened functions at the primary cilium. Nature 437, 1018-1021 (2005). (Pubitemid 41486982)
31. Katritch, V., Cherezov, V. & Stevens, R. C. Diversity and modularity of G protein-coupled receptor structures. Trends Pharmacol. Sci. 33, 17-27 (2012).
32. Riobo, N. A., Saucy, B., Dilizio, C. & Manning, D. R. Activation of heterotrimeric G proteins by Smoothened. Proc. Natl Acad. Sci. USA 103, 12607-12612 (2006). (Pubitemid 44267306)
33. Rasmussen, S. G. et al. Crystal structure of the beta2 adrenergic receptor-Gs protein complex. Nature 477, 549-555 (2011).
34. Katritch, V., Cherezov, V. & Stevens, R. C. Structure-function of the G proteincoupled receptor superfamily. Annu. Rev. Pharmacol. Toxicol. 53, 531-556 (2013).
35. Wang, C. et al. Structural basis for molecular recognition at serotonin receptors. Science 340, 610-614 (2013).
36. Wacker, D. et al. Structural features for functional selectivity at serotonin receptors. Science 340, 615-619 (2013).
37. White, J. F. et al. Structure of the agonist-bound neurotensin receptor. Nature 490, 508-513 (2012).
38. Xu, F. et al. Structure of an agonist-bound human A2A adenosine receptor. Science 332, 322-327 (2011).
39. Yao, X. J. et al. The effect of ligand efficacy on the formation and stability of a GPCR-G protein complex. Proc. Natl Acad. Sci. USA 106, 9501-9506 (2009).
40. Warne, T. et al. The structural basis for agonist and partial agonist action on a beta(1)-adrenergic receptor. Nature 469, 241-244 (2011).
41. Rana, R. et al. Structural insights into the role of the Smoothened cysteine-rich domain in Hedgehog signalling. Nat. Commun. 4, 2965 (2013).
42. Hanson, M. A. et al. A specific cholesterol binding site is established by the 2.8 A structure of the human beta2-adrenergic receptor. Structure 16, 897-905 (2008). (Pubitemid 351778384)
43. Jaakola, V. P. et al. The 2.6 angstrom crystal structure of a human A2A adenosine receptor bound to an antagonist. Science 322, 1211-1217 (2008).
44. Manglik, A. et al. Crystal structure of the micro-opioid receptor bound to a morphinan antagonist. Nature 485, 321-326 (2012).
45. Caffrey, M. & Cherezov, V. Crystallizing membrane proteins using lipidic mesophases. Nat. Protoc. 4, 706-731 (2009).
46. Cherezov, V., Peddi, A., Muthusubramaniam, L., Zheng, Y. F. & Caffrey, M. A robotic system for crystallizing membrane and soluble proteins in lipidic mesophases. Acta Crystallogr. D Biol. Crystallogr. 60, 1795-1807 (2004). (Pubitemid 41079701)
47. Cherezov, V. et al. Rastering strategy for screening and centring of microcrystal samples of human membrane proteins with a sub-10 microm size X-ray synchrotron beam. J. R. Soc. Interface 6(Suppl 5): S587-S597 (2009).
48. Otwinowski, Z. & Minor, W. Processing of X-ray diffraction data collected in oscillation mode. Methods Enzymol. 276, 307-326 (1997). (Pubitemid 27085611)
49. McCoy, A. J. et al. Phaser crystallographic software. J. Appl. Crystallogr. 40, 658-674 (2007). (Pubitemid 47080256)
50. Murshudov, G. N., Vagin, A. A. & Dodson, E. J. Refinement of macromolecular structures by the maximum-likelihood method. Acta Crystallogr. D Biol. Crystallogr. 53, 240-255 (1997). (Pubitemid 27235885)
51. BUSTER v. 2.8.0 (Global Phasing Ltd, Cambridge, U.K. (2009).
52. Emsley, P., Lohkamp, B., Scott, W. G. & Cowtan, K. Features and development of Coot. Acta. Crystallogr. D Biol. Crystallogr. 66, 486-501 (2010).
53. Bhat, T. N. & Cohen, G. H. Omitmap-an electron-density map suitable for the examination of errors in a macromolecular model. J. Appl. Crystallogr. 17, 244-248 (1984). (Pubitemid 15474433)
54. Bhat, T. N. Calculation of an Omit Map. J. Appl. Crystallogr. 21, 279-281 (1988).
55. ICM Manual v. 3.0 (MolSoft LLC, La Jolla, CA (2012).
56. Totrov, M. & Abagyan, R. Flexible protein-ligand docking by global energy optimization in internal coordinates. Proteins (Suppl 1): 215-220 (1997). (Pubitemid 28090502)