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Evaluation of synthetic FK506 analogues as ligands for the FK506-binding proteins 51 and 52.

Gopalakrishnan R, Kozany C, Gaali S, Kress C, Hoogeland B, Bracher A, Hausch F
J Med Chem 55 4114-22 (2012)
Related entries: 4drm, 4drn, 4dro, 4drp

Cited: 30 times
EuropePMC logo PMID: 22455444

Abstract

The FK506-binding proteins (FKBP) 51 and 52 are cochaperones that modulate the signal transduction of steroid hormone receptors. Both proteins have been implicated in prostate cancer. Furthermore, single nucleotide polymorphisms in the gene encoding FKBP51 have been associated with a variety of psychiatric disorders. Rapamycin and FK506 are two macrocyclic natural products that bind to these proteins indiscriminately but with nanomolar affinity. We here report the cocrystal structure of FKBP51 with a simplified α-ketoamide analogue derived from FK506 and the first structure-activity relationship analysis for FKBP51 and FKBP52 based on this compound. In particular, the tert-pentyl group of this ligand was systematically replaced by a cyclohexyl ring system, which more closely resembles the pyranose ring in the high-affinity ligands rapamycin and FK506. The interaction with FKBPs was found to be surprisingly tolerant to the stereochemistry of the attached cyclohexyl substituents. The molecular basis for this tolerance was elucidated by X-ray cocrystallography.

Reviews - 4drk mentioned but not cited (1)

  1. Roles of Prolyl Isomerases in RNA-Mediated Gene Expression. Thapar R. Biomolecules 5 974-999 (2015)

Articles - 4drk mentioned but not cited (2)

  1. Targeted Covalent Inhibition of Plasmodium FK506 Binding Protein 35. Atack TC, Raymond DD, Blomquist CA, Pasaje CF, McCarren PR, Moroco J, Befekadu HB, Robinson FP, Pal D, Esherick LY, Ianari A, Niles JC, Sellers WR. ACS Med Chem Lett 11 2131-2138 (2020)
  2. Crystal structure and conformational flexibility of the unligated FK506-binding protein FKBP12.6. Chen H, Mustafi SM, LeMaster DM, Li Z, Héroux A, Li H, Hernández G. Acta Crystallogr D Biol Crystallogr 70 636-646 (2014)


Reviews citing this publication (9)

  1. Is the HPA Axis as Target for Depression Outdated, or Is There a New Hope? Menke A. Front Psychiatry 10 101 (2019)
  2. FKBP Ligands-Where We Are and Where to Go? Kolos JM, Voll AM, Bauder M, Hausch F. Front Pharmacol 9 1425 (2018)
  3. Peptidyl-Proline Isomerases (PPIases): Targets for Natural Products and Natural Product-Inspired Compounds. Dunyak BM, Gestwicki JE. J Med Chem 59 9622-9644 (2016)
  4. The Many Faces of FKBP51. Hähle A, Merz S, Meyners C, Hausch F. Biomolecules 9 E35 (2019)
  5. Functional diversity and pharmacological profiles of the FKBPs and their complexes with small natural ligands. Galat A. Cell Mol Life Sci 70 3243-3275 (2013)
  6. Steroid Receptor-Associated Immunophilins: A Gateway to Steroid Signalling. Ratajczak T, Cluning C, Ward BK. Clin Biochem Rev 36 31-52 (2015)
  7. Precision pharmacotherapy: psychiatry's future direction in preventing, diagnosing, and treating mental disorders. Menke A. Pharmgenomics Pers Med 11 211-222 (2018)
  8. FK506-binding protein 12 ligands: a patent review. Liu F, Wang YQ, Meng L, Gu M, Tan RY. Expert Opin Ther Pat 23 1435-1449 (2013)
  9. Analysis of the Selective Antagonist SAFit2 as a Chemical Probe for the FK506-Binding Protein 51. Buffa V, Knaup FH, Heymann T, Springer M, Schmidt MV, Hausch F. ACS Pharmacol Transl Sci 6 361-371 (2023)

Articles citing this publication (18)

  1. Selective inhibitors of the FK506-binding protein 51 by induced fit. Gaali S, Kirschner A, Cuboni S, Hartmann J, Kozany C, Balsevich G, Namendorf C, Fernandez-Vizarra P, Sippel C, Zannas AS, Draenert R, Binder EB, Almeida OF, Rühter G, Uhr M, Schmidt MV, Touma C, Bracher A, Hausch F. Nat Chem Biol 11 33-37 (2015)
  2. Large FK506-binding proteins shape the pharmacology of rapamycin. März AM, Fabian AK, Kozany C, Bracher A, Hausch F. Mol Cell Biol 33 1357-1367 (2013)
  3. Pharmacological Inhibition of the Psychiatric Risk Factor FKBP51 Has Anxiolytic Properties. Hartmann J, Wagner KV, Gaali S, Kirschner A, Kozany C, Rühter G, Dedic N, Häusl AS, Hoeijmakers L, Westerholz S, Namendorf C, Gerlach T, Uhr M, Chen A, Deussing JM, Holsboer F, Hausch F, Schmidt MV. J Neurosci 35 9007-9016 (2015)
  4. FKBPs and the Akt/mTOR pathway. Hausch F, Kozany C, Theodoropoulou M, Fabian AK. Cell Cycle 12 2366-2370 (2013)
  5. Crystal structures of the free and ligand-bound FK1-FK2 domain segment of FKBP52 reveal a flexible inter-domain hinge. Bracher A, Kozany C, Hähle A, Wild P, Zacharias M, Hausch F. J Mol Biol 425 4134-4144 (2013)
  6. Molecular dynamics simulation, binding free energy calculation and unbinding pathway analysis on selectivity difference between FKBP51 and FKBP52: Insight into the molecular mechanism of isoform selectivity. Shi D, Bai Q, Zhou S, Liu X, Liu H, Yao X. Proteins 86 43-56 (2018)
  7. Analysis of FK506, timcodar (VX-853) and FKBP51 and FKBP52 chaperones in control of glucocorticoid receptor activity and phosphorylation. Hinds TD, Stechschulte LA, Elkhairi F, Sanchez ER. Pharmacol Res Perspect 2 e00076 (2014)
  8. Differential conformational dynamics in the closely homologous FK506-binding domains of FKBP51 and FKBP52. Mustafi SM, LeMaster DM, Hernández G. Biochem J 461 115-123 (2014)
  9. Rational design and asymmetric synthesis of potent and neurotrophic ligands for FK506-binding proteins (FKBPs). Pomplun S, Wang Y, Kirschner A, Kozany C, Bracher A, Hausch F. Angew Chem Int Ed Engl 54 345-348 (2015)
  10. Alchemical determination of drug-receptor binding free energy: Where we stand and where we could move to. Procacci P. J Mol Graph Model 71 233-241 (2017)
  11. Timcodar (VX-853) Is a Non-FKBP12 Binding Macrolide Derivative That Inhibits PPARγ and Suppresses Adipogenesis. Hinds TD, John K, McBeth L, Trabbic CJ, Sanchez ER. PPAR Res 2016 6218637 (2016)
  12. The seven pillars of molecular pharmacology: GPCR research honored with Nobel Prize for chemistry. Hausch F, Holsboer F. Angew Chem Int Ed Engl 51 12172-12175 (2012)
  13. Studies on the constituents of Helleborus purpurascens: analysis and biological activity of the aqueous and organic extracts. Franz MH, Birzoi R, Maftei CV, Maftei E, Kelter G, Fiebig HH, Neda I. Amino Acids 50 163-188 (2018)
  14. C-H…O hydrogen bonds in FK506-binding protein-ligand interactions. Rajan S, Baek K, Yoon HS. J Mol Recognit 26 550-555 (2013)
  15. FKBP51 and FKBP12.6-Novel and tight interactors of Glomulin. Hähle A, Geiger TM, Merz S, Meyners C, Tianqi M, Kolos J, Hausch F. PLoS One 14 e0221926 (2019)
  16. Binding pocket stabilization by high-throughput screening of yeast display libraries. Lerma Romero JA, Meyners C, Christmann A, Reinbold LM, Charalampidou A, Hausch F, Kolmar H. Front Mol Biosci 9 1023131 (2022)
  17. Discovery of pentapeptide-inhibitor hits targeting FKBP51 by combining computational modeling and X-ray crystallography. Han JT, Zhu Y, Pan DB, Xue HX, Wang S, Peng Y, Liu H, He YX, Yao X. Comput Struct Biotechnol J 19 4079-4091 (2021)
  18. Local blockade of tacrolimus promotes T-cell-mediated tumor regression in systemically immunosuppressed hosts. Veitch M, Beaumont K, Pouwer R, Chew HY, Frazer IH, Soyer HP, Campbell S, Dymock BW, Harvey A, Cock TA, Wells JW. J Immunother Cancer 11 e006783 (2023)


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