lnu.sePublications
Change search
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • harvard1
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
Activation and Inactivation of the FLT3 Kinase: Pathway Intermediates and the Free Energy of Transition
Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. (Linnaeus Ctr Biomat Chem, BMC;CCBG)ORCID iD: 0000-0001-9871-413X
Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. (Linnaeus Ctr Biomat Chem, BMC;CCBG)ORCID iD: 0000-0001-8696-3104
2019 (English)In: Journal of Physical Chemistry B, ISSN 1520-6106, E-ISSN 1520-5207, Vol. 123, no 26, p. 5385-5394Article in journal (Refereed) Published
Abstract [en]

The aberrant expression of kinases is often associated with pathologies such as cancer and autoimmune diseases. Like other types of enzymes, kinases can adopt active and inactive states, where a shift toward more stable active state often leads to disease. Dozens of kinase inhibitors are, therefore, used as drugs. Most of these bind to either the inactive or active state. In this work, we study the transitions between these two states in FLT3, an important drug target in leukemias. Kinases are composed of two lobes (N- and C-terminal lobes) with the catalytic site in-between. Through projection of the largest motions obtained through molecular dynamics (MD) simulations, we show that each of the end-states (active or inactive) already possess the ability for transition as the two lobes rotate which initiates the transition. A targeted simulation approach known as essential dynamics sampling (EDS) was used to speed up the transition between the two protein states. Coupling the EDS to implicit-solvent MD was performed to estimate the free energy barriers of the transitions. The activation energies were found in good agreement with previous estimates obtained for other kinases. Finally, we identified FLT3 intermediates that assumed configurations that resemble that of the c-Src nonreceptor tyrosine kinase. The intermediates show better binding to the drug ponatinib than c-Src and the inactive state of FLT3. This suggests that targeting intermediate states can be used to explain the drug-binding patterns of kinases and for rational drug design.

Place, publisher, year, edition, pages
American Chemical Society (ACS), 2019. Vol. 123, no 26, p. 5385-5394
National Category
Theoretical Chemistry Physical Chemistry Biophysics
Research subject
Chemistry, Physical Chemistry
Identifiers
URN: urn:nbn:se:lnu:diva-86904DOI: 10.1021/acs.jpcb.9b01567ISI: 000474796300001PubMedID: 31244095OAI: oai:DiVA.org:lnu-86904DiVA, id: diva2:1337874
Available from: 2019-07-18 Created: 2019-07-18 Last updated: 2019-07-25Bibliographically approved

Open Access in DiVA

No full text in DiVA

Other links

Publisher's full textPubMed

Authority records BETA

Todde, GuidoFriedman, Ran

Search in DiVA

By author/editor
Todde, GuidoFriedman, Ran
By organisation
Department of Chemistry and Biomedical Sciences
In the same journal
Journal of Physical Chemistry B
Theoretical ChemistryPhysical ChemistryBiophysics

Search outside of DiVA

GoogleGoogle Scholar

doi
pubmed
urn-nbn

Altmetric score

doi
pubmed
urn-nbn
Total: 27 hits
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • harvard1
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf