Combined x-ray crystallography and computational modeling approach to investigate the Hsp90 C-terminal peptide binding to FKBP51

Scientific Reports
Rajnish KumarPavel F Pavlov

Abstract

FK506 binding protein of 51 kDa (FKBP51) is a heat shock protein 90 (Hsp90) co-chaperone involved in the regulation of steroid hormone receptors activity. It is known for its role in various regulatory pathways implicated in mood and stress-related disorders, cancer, obesity, Alzheimer's disease and corticosteroid resistant asthma. It consists of two FKBP12 like active peptidyl prolyl isomerase (PPIase) domains (an active FK1 and inactive FK2 domain) and one tetratricopeptide repeat (TPR) domain that mediates interaction with Hsp90 via its C-terminal MEEVD peptide. Here, we report a combined x-ray crystallography and molecular dynamics study to reveal the binding mechanism of Hsp90 MEEVD peptide to the TPR domain of FKBP51. The results demonstrated that the Hsp90 C-terminal peptide binds to the TPR domain of FKBP51 with the help of di-carboxylate clamp involving Lys272, Glu273, Lys352, Asn322, and Lys329 which are conserved throughout several di-carboxylate clamp TPR proteins. Interestingly, the results from molecular dynamics study are also in agreement to the complex structure where all the contacts between these two partners were consistent throughout the simulation period. In a nutshell, our findings provide new opportunity...Continue Reading

References

Nov 1, 1995·Protein Science : a Publication of the Protein Society·S Itoh, M A Navia
Feb 17, 1998·Protein Engineering·D XuR Nussinov
Jan 23, 2003·Proceedings of the National Academy of Sciences of the United States of America·Cindy R SinarsJon Clardy
Jan 31, 2003·Proteins·Simon C LovellDavid C Richardson
Jul 23, 2003·Current Topics in Medicinal Chemistry·M Avramut, C L Achim
Dec 9, 2003·Trends in Biochemical Sciences·Luca D D'Andrea, Lynne Regan
May 26, 2004·Proceedings of the National Academy of Sciences of the United States of America·Beili WuZihe Rao
Dec 2, 2004·Acta Crystallographica. Section D, Biological Crystallography·E Krissinel, K Henrick
May 13, 2006·Proceedings of the National Academy of Sciences of the United States of America·Michael StrongDavid Eisenberg
Jan 11, 2007·The Journal of Chemical Physics·Giovanni BussiMichele Parrinello
Feb 17, 2007·The Journal of Clinical Investigation·Chad A DickeyLeonard Petrucelli
May 23, 2007·Nucleic Acids Research·Markus Wiederstein, Manfred J Sippl
Oct 13, 2007·Proteins·Pascal BenkertDietmar Schomburg
Oct 24, 2007·The International Journal of Biochemistry & Cell Biology·Terry D Hinds, Edwin R Sánchez
Sep 13, 2008·ACS Chemical Biology·Fang Yi, Lynne Regan
Jan 27, 2009·BMC Bioinformatics·Georg SteinkellnerKarl Gruber
Aug 1, 2007·Journal of Applied Crystallography·Airlie J McCoyRandy J Read
Jan 9, 2010·Acta Crystallographica. Section D, Biological Crystallography·Vincent B ChenDavid C Richardson
Jan 15, 2010·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Umesh K JinwalChad A Dickey
Feb 4, 2010·Acta Crystallographica. Section D, Biological Crystallography·Paul D AdamsPeter H Zwart
Apr 13, 2010·Acta Crystallographica. Section D, Biological Crystallography·P EmsleyK Cowtan
Apr 5, 2011·Acta Crystallographica. Section D, Biological Crystallography·Martyn D WinnKeith S Wilson
Apr 5, 2011·Acta Crystallographica. Section D, Biological Crystallography·Clemens VonrheinGérard Bricogne
Sep 17, 2011·Journal of Chemical Information and Modeling·Roman A Laskowski, Mark B Swindells
Sep 22, 2011·PloS One·John C O'LearyChad A Dickey
May 1, 2012·Bioinformatics·Douglas L Theobald, Phillip A Steindel
Jan 30, 2013·Molecular and Cellular Biology·Andreas M MärzFelix Hausch
Jun 4, 2013·Journal of Molecular Biology·Veronika HaslbeckKlaus Richter
Sep 4, 2013·The Journal of Clinical Investigation·Laura J BlairChad A Dickey
Oct 7, 2014·Journal of Visualized Experiments : JoVE·Mirella VivoliNicholas J Harmer
Dec 2, 2014·Nature Chemical Biology·Steffen GaaliFelix Hausch
Dec 10, 2014·Sub-cellular Biochemistry·Adrienne L Edkins
Apr 25, 2015·Nucleic Acids Research·Eugene Krissinel

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Citations

Dec 6, 2017·International Journal of Molecular Sciences·Gabriel R FriesTheo Rein
Jan 24, 2019·Biomolecules·Andreas HähleFelix Hausch
Feb 23, 2019·The Journal of Histochemistry and Cytochemistry : Official Journal of the Histochemistry Society·Deborah RotoliPablo Martín-Vasallo
Nov 2, 2018·Nature Communications·Javier OrozMarkus Zweckstetter
Dec 21, 2018·Frontiers in Pharmacology·Jürgen M KolosFelix Hausch

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Methods Mentioned

BETA
protein folding
x-ray crystallography
PISA
isothermal
surface plasmon resonance
PCR
FRET

Software Mentioned

Phenix
COOT
MolProbity
Theseus
QMEAN4
ProSA
CCP4
Bio
QMEAN
PyMOL

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