دورية أكاديمية
GQ-16, a novel peroxisome proliferator-activated receptor γ (PPARγ) ligand, promotes insulin sensitization without weight gain.
| العنوان: | GQ-16, a novel peroxisome proliferator-activated receptor γ (PPARγ) ligand, promotes insulin sensitization without weight gain. |
|---|---|
| المؤلفون: | Amato AA; Laboratório de Farmacologia Molecular, Departamento de Ciências Farmacêuticas, Faculdade de Ciências da Saúde, Universidade de Brasília, 70919-970 Brazil., Rajagopalan S, Lin JZ, Carvalho BM, Figueira AC, Lu J, Ayers SD, Mottin M, Silveira RL, Souza PC, Mourão RH, Saad MJ, Togashi M, Simeoni LA, Abdalla DS, Skaf MS, Polikparpov I, Lima MC, Galdino SL, Brennan RG, Baxter JD, Pitta IR, Webb P, Phillips KJ, Neves FA |
| المصدر: | The Journal of biological chemistry [J Biol Chem] 2012 Aug 10; Vol. 287 (33), pp. 28169-79. Date of Electronic Publication: 2012 May 14. |
| نوع المنشور: | Journal Article; Research Support, Non-U.S. Gov't |
| اللغة: | English |
| بيانات الدورية: | Publisher: Elsevier Inc. on behalf of American Society for Biochemistry and Molecular Biology Country of Publication: United States NLM ID: 2985121R Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1083-351X (Electronic) Linking ISSN: 00219258 NLM ISO Abbreviation: J Biol Chem Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: 2021- : [New York, NY] : Elsevier Inc. on behalf of American Society for Biochemistry and Molecular Biology Original Publication: Baltimore, MD : American Society for Biochemistry and Molecular Biology |
| مواضيع طبية MeSH: | Weight Gain*, Hypoglycemic Agents/*pharmacology , PPAR gamma/*agonists , Thiazolidinediones/*pharmacology, 3T3-L1 Cells ; Animals ; Cyclin-Dependent Kinase 5/genetics ; Cyclin-Dependent Kinase 5/metabolism ; Drug Evaluation, Preclinical ; Humans ; Hypoglycemic Agents/chemistry ; Hypoglycemic Agents/pharmacokinetics ; Ligands ; Mice ; NIH 3T3 Cells ; PPAR gamma/genetics ; PPAR gamma/metabolism ; Phosphorylation/drug effects ; Phosphorylation/genetics ; Protein Structure, Secondary ; Thiazolidinediones/chemistry ; Thiazolidinediones/pharmacokinetics ; U937 Cells |
| مستخلص: | The recent discovery that peroxisome proliferator-activated receptor γ (PPARγ) targeted anti-diabetic drugs function by inhibiting Cdk5-mediated phosphorylation of the receptor has provided a new viewpoint to evaluate and perhaps develop improved insulin-sensitizing agents. Herein we report the development of a novel thiazolidinedione that retains similar anti-diabetic efficacy as rosiglitazone in mice yet does not elicit weight gain or edema, common side effects associated with full PPARγ activation. Further characterization of this compound shows GQ-16 to be an effective inhibitor of Cdk5-mediated phosphorylation of PPARγ. The structure of GQ-16 bound to PPARγ demonstrates that the compound utilizes a binding mode distinct from other reported PPARγ ligands, although it does share some structural features with other partial agonists, such as MRL-24 and PA-082, that have similarly been reported to dissociate insulin sensitization from weight gain. Hydrogen/deuterium exchange studies reveal that GQ-16 strongly stabilizes the β-sheet region of the receptor, presumably explaining the compound's efficacy in inhibiting Cdk5-mediated phosphorylation of Ser-273. Molecular dynamics simulations suggest that the partial agonist activity of GQ-16 results from the compound's weak ability to stabilize helix 12 in its active conformation. Our results suggest that the emerging model, whereby "ideal" PPARγ-based therapeutics stabilize the β-sheet/Ser-273 region and inhibit Cdk5-mediated phosphorylation while minimally invoking adipogenesis and classical agonism, is indeed a valid framework to develop improved PPARγ modulators that retain antidiabetic actions while minimizing untoward effects. |
| References: | Mol Cell. 2000 Mar;5(3):545-55. (PMID: 10882139) Diabetes Care. 2007 Jun;30(6):1574-6. (PMID: 17363747) J Biol Chem. 1995 Jun 2;270(22):12953-6. (PMID: 7768881) Nat Med. 2011 May;17(5):618-22. (PMID: 21532596) Nature. 1998 Sep 10;395(6698):137-43. (PMID: 9744270) J Comput Chem. 2005 Dec;26(16):1781-802. (PMID: 16222654) Bioorg Med Chem Lett. 2005 Jan 17;15(2):357-62. (PMID: 15603954) N Engl J Med. 2007 Jun 14;356(24):2457-71. (PMID: 17517853) Cell. 1994 Dec 30;79(7):1147-56. (PMID: 8001151) Acta Crystallogr D Biol Crystallogr. 2010 Feb;66(Pt 2):213-21. (PMID: 20124702) Methods Enzymol. 2005;402:312-60. (PMID: 16401514) Nat Med. 2011 May;17(5):623-6. (PMID: 21532595) J Appl Crystallogr. 2007 Aug 1;40(Pt 4):658-674. (PMID: 19461840) Cell Metab. 2012 Mar 7;15(3):395-404. (PMID: 22405074) Endocr Rev. 2006 Dec;27(7):762-78. (PMID: 17056740) Structure. 2007 Oct;15(10):1258-71. (PMID: 17937915) Nature. 2008 Nov 20;456(7220):350-6. (PMID: 19043829) Acta Crystallogr D Biol Crystallogr. 1994 Sep 1;50(Pt 5):760-3. (PMID: 15299374) Eur J Med Chem. 2005 Nov;40(11):1129-33. (PMID: 16040159) Nucleic Acids Res. 2005 Jul 1;33(Web Server issue):W368-71. (PMID: 15980491) Trends Biochem Sci. 2004 Jun;29(6):317-24. (PMID: 15276186) J Mol Graph. 1996 Feb;14(1):33-8, 27-8. (PMID: 8744570) J Clin Endocrinol Metab. 2006 Sep;91(9):3349-54. (PMID: 16608888) Annu Rev Biochem. 2001;70:341-67. (PMID: 11395411) J Phys Chem B. 1998 Apr 30;102(18):3586-616. (PMID: 24889800) Nature. 2010 Jul 22;466(7305):451-6. (PMID: 20651683) J Nutr. 2000 Dec;130(12):3116S-3121S. (PMID: 11110883) BMC Bioinformatics. 2007 Aug 22;8:306. (PMID: 17714583) J Clin Endocrinol Metab. 1989 Feb;68(2):374-8. (PMID: 2645308) Anal Chem. 1999 Jul 15;71(14):2871-82. (PMID: 10424174) Endocrinology. 2005 Mar;146(3):1226-35. (PMID: 15591153) Acta Crystallogr D Biol Crystallogr. 2010 Apr;66(Pt 4):486-501. (PMID: 20383002) J Clin Invest. 2007 Sep;117(9):2621-37. (PMID: 17717599) Proc Natl Acad Sci U S A. 2005 Jun 28;102(26):9406-11. (PMID: 15956187) Mol Endocrinol. 2006 Apr;20(4):809-30. (PMID: 16373399) Nature. 2011 Sep 04;477(7365):477-81. (PMID: 21892191) J Clin Invest. 2000 Aug;106(4):467-72. (PMID: 10953021) Obes Res. 2003 Jan;11(1):65-74. (PMID: 12529487) Eur J Med Chem. 2007 Oct;42(10):1263-71. (PMID: 17448573) Mol Endocrinol. 2011 Jan;25(1):15-31. (PMID: 21106879) J Clin Endocrinol Metab. 2007 Apr;92(4):1305-10. (PMID: 17264176) |
| سلسلة جزيئية: | PDB 3T03 |
| المشرفين على المادة: | 0 (5-(5-bromo-2-methoxybenzylidene)-3-(4-methyl-benzyl)thiazolidine-2,4-dione) 0 (Hypoglycemic Agents) 0 (Ligands) 0 (PPAR gamma) 0 (Thiazolidinediones) EC 2.7.11.1 (Cyclin-Dependent Kinase 5) EC 2.7.11.22 (CDK5 protein, human) EC 2.7.11.22 (Cdk5 protein, mouse) |
| تواريخ الأحداث: | Date Created: 20120516 Date Completed: 20121105 Latest Revision: 20211021 |
| رمز التحديث: | 20221213 |
| مُعرف محوري في PubMed: | PMC3431672 |
| DOI: | 10.1074/jbc.M111.332106 |
| PMID: | 22584573 |
| قاعدة البيانات: | MEDLINE |
| تدمد: | 1083-351X |
|---|---|
| DOI: | 10.1074/jbc.M111.332106 |