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Structural characterization of the PPIase domain of FKBP51, a cochaperone of human Hsp90.

Bracher A, Kozany C, Thost AK, Hausch F
Acta Crystallogr D Biol Crystallogr 67 549-59 (2011)
Related entries: 3o5d, 3o5e, 3o5f, 3o5g, 3o5i, 3o5j, 3o5k, 3o5l, 3o5m, 3o5o, 3o5q, 3o5r

Cited: 37 times
EuropePMC logo PMID: 21636895

Abstract

Steroid hormone receptors are key components of mammalian stress and sex hormone systems. Many of them rely on the Hsp90 chaperone system for full function and are further fine-tuned by Hsp90-associated peptidyl-prolyl isomerases such as FK506-binding proteins 51 and 52. FK506-binding protein 51 (FKBP51) has been shown to reduce glucocorticoid receptor signalling and has been genetically associated with human stress resilience and with numerous psychiatric disorders. The peptidyl-prolyl isomerase domain of FKBP51 contains a high-affinity binding site for the natural products FK506 and rapamycin and has further been shown to convey most of the inhibitory activity on the glucocorticoid receptor. FKBP51 has therefore become a prime new target for the treatment of stress-related affective disorders that could be amenable to structure-based drug design. Here, a series of high-resolution structures of the peptidyl-prolyl isomerase domain of FKBP51 as well as a cocrystal structure with the prototypic ligand FK506 are described. These structures provide a detailed picture of the drug-binding domain of FKBP51 and the molecular binding mode of its ligand as a starting point for the rational design of improved inhibitors.

Reviews - 3o5p mentioned but not cited (1)

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

Articles - 3o5p mentioned but not cited (10)

  1. Fast and anisotropic flexibility-rigidity index for protein flexibility and fluctuation analysis. Opron K, Xia K, Wei GW. J Chem Phys 140 234105 (2014)
  2. Ab initio solution of macromolecular crystal structures without direct methods. McCoy AJ, Oeffner RD, Wrobel AG, Ojala JR, Tryggvason K, Lohkamp B, Read RJ. Proc Natl Acad Sci U S A 114 3637-3641 (2017)
  3. 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)
  4. Blind prediction of protein B-factor and flexibility. Bramer D, Wei GW. J Chem Phys 149 134107 (2018)
  5. Statistical allosteric coupling to the active site indole ring flip equilibria in the FK506-binding domain. Anderson JS, Mustafi SM, Hernández G, LeMaster DM. Biophys Chem 192 41-48 (2014)
  6. Atom-specific persistent homology and its application to protein flexibility analysis. Bramer D, Wei GW. Comput Math Biophys 8 1-35 (2020)
  7. 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)
  8. Transient conformations in the unliganded FK506 binding domain of FKBP51 correspond to two distinct inhibitor-bound states. Anderson JS, LeMaster DM, Hernández G. J Biol Chem 299 105159 (2023)
  9. 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)
  10. The oxygen-oxygen distance of water in crystallographic data sets. Palese LL. Data Brief 28 105076 (2020)


Reviews citing this publication (8)

  1. FKBP Ligands-Where We Are and Where to Go? Kolos JM, Voll AM, Bauder M, Hausch F. Front Pharmacol 9 1425 (2018)
  2. The FKBP51 Glucocorticoid Receptor Co-Chaperone: Regulation, Function, and Implications in Health and Disease. Fries GR, Gassen NC, Rein T. Int J Mol Sci 18 E2614 (2017)
  3. The Many Faces of FKBP51. Hähle A, Merz S, Meyners C, Hausch F. Biomolecules 9 E35 (2019)
  4. Diverse structures, functions and uses of FK506 binding proteins. Bonner JM, Boulianne GL. Cell Signal 38 97-105 (2017)
  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. Conformational Dynamics in FKBP Domains: Relevance to Molecular Signaling and Drug Design. LeMaster DM, Hernandez G. Curr Mol Pharmacol 9 5-26 (2015)
  7. 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)
  8. Scaffold proteins of cancer signaling networks: The paradigm of FK506 binding protein 51 (FKBP51) supporting tumor intrinsic properties and immune escape. Marrone L, D'Agostino M, Giordano C, Giacomo VD, Urzini S, Malasomma C, Gammella MP, Tufano M, Romano S, Romano MF. Oncol Res 31 423-436 (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. The prospect of FKBP51 as a drug target. Schmidt MV, Paez-Pereda M, Holsboer F, Hausch F. ChemMedChem 7 1351-1359 (2012)
  3. FKBPs and the Akt/mTOR pathway. Hausch F, Kozany C, Theodoropoulou M, Fabian AK. Cell Cycle 12 2366-2370 (2013)
  4. 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)
  5. 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)
  6. Coupling of Conformational Transitions in the N-terminal Domain of the 51-kDa FK506-binding Protein (FKBP51) Near Its Site of Interaction with the Steroid Receptor Proteins. LeMaster DM, Mustafi SM, Brecher M, Zhang J, Héroux A, Li H, Hernández G. J Biol Chem 290 15746-15757 (2015)
  7. Macrocyclic FKBP51 Ligands Define a Transient Binding Mode with Enhanced Selectivity. Voll AM, Meyners C, Taubert MC, Bajaj T, Heymann T, Merz S, Charalampidou A, Kolos J, Purder PL, Geiger TM, Wessig P, Gassen NC, Bracher A, Hausch F. Angew Chem Int Ed Engl 60 13257-13263 (2021)
  8. Development of NanoBRET-Binding Assays for FKBP-Ligand Profiling in Living Cells. Gnatzy MT, Geiger TM, Kuehn A, Gutfreund N, Walz M, Kolos JM, Hausch F. Chembiochem 22 2257-2261 (2021)
  9. Accelerated flexible protein-ligand docking using Hamiltonian replica exchange with a repulsive biasing potential. Ostermeir K, Zacharias M. PLoS One 12 e0172072 (2017)
  10. C-H…O hydrogen bonds in FK506-binding protein-ligand interactions. Rajan S, Baek K, Yoon HS. J Mol Recognit 26 550-555 (2013)
  11. Rapamycin inhibits AR signaling pathway in prostate cancer by interacting with the FK1 domain of FKBP51. Zhang J, Wu D, He Y, Li L, Liu S, Lu J, Gui H, Wang Y, Tao Y, Wang H, Kaushik D, Rodriguez R, Wang Z. Biochem Biophys Rep 23 100778 (2020)
  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. Fenton-Chemistry-Based Oxidative Modification of Proteins Reflects Their Conformation. Nehls T, Heymann T, Meyners C, Hausch F, Lermyte F. Int J Mol Sci 22 9927 (2021)
  14. 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)
  15. Enantioselective Synthesis of a Tricyclic, sp3 -Rich Diazatetradecanedione: an Amino Acid-Based Natural Product-Like Scaffold. Bischoff M, Mayer P, Meyners C, Hausch F. Chemistry 26 4677-4681 (2020)
  16. 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)
  17. Large-scale, in-cell photocrosslinking at single-residue resolution reveals the molecular basis for glucocorticoid receptor regulation by immunophilins. Baischew A, Engel S, Taubert MC, Geiger TM, Hausch F. Nat Struct Mol Biol 30 1857-1866 (2023)
  18. Deconstructing Protein Binding of Sulfonamides and Sulfonamide Analogues. Purder PL, Meyners C, Sugiarto WO, Kolos J, Löhr F, Gebel J, Nehls T, Dötsch V, Lermyte F, Hausch F. JACS Au 3 2478-2486 (2023)


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