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Todde, Guido
Publications (4 of 4) Show all publications
Todde, G. & Friedman, R. (2019). Activation and Inactivation of the FLT3 Kinase: Pathway Intermediates and the Free Energy of Transition. Journal of Physical Chemistry B, 123(26), 5385-5394
Open this publication in new window or tab >>Activation and Inactivation of the FLT3 Kinase: Pathway Intermediates and the Free Energy of Transition
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
National Category
Theoretical Chemistry Physical Chemistry Biophysics
Research subject
Chemistry, Physical Chemistry
Identifiers
urn:nbn:se:lnu:diva-86904 (URN)10.1021/acs.jpcb.9b01567 (DOI)000474796300001 ()31244095 (PubMedID)
Available from: 2019-07-18 Created: 2019-07-18 Last updated: 2019-07-25Bibliographically approved
Todde, G. & Friedman, R. (2019). Conformational modifications induced by internal tandem duplications on the FLT3 kinase and juxtamembrane domains. Physical Chemistry, Chemical Physics - PCCP, 21(34), 18467-18476
Open this publication in new window or tab >>Conformational modifications induced by internal tandem duplications on the FLT3 kinase and juxtamembrane domains
2019 (English)In: Physical Chemistry, Chemical Physics - PCCP, ISSN 1463-9076, E-ISSN 1463-9084, Vol. 21, no 34, p. 18467-18476Article in journal (Refereed) Published
Abstract [en]

he aberrant expression of FLT3 tyrosine kinase is associated primarily with acute myeloid leukaemia. This blood malignancy is often related to the onset of internal tandem duplications (ITDs) in the native sequence of the protein. The ITDs occur mainly in the juxtamembrane domain of the protein and alter the normal activity of the enzyme. In this work, we have studied the native form of FLT3 and six mutants by molecular dynamics simulations. The catalytic activity of FLT3 is exerted by the tyrosine kinase domain (KD) and regulated by the juxtamembrane (JM) domain. Analysis of the dynamics of these two domains have shown that the introduction of ITDs in the JM domain alters both structural and dynamic parameters. The presence of ITDs allowed the protein to span a larger portion of the conformational space, particularly in the JM domain and the activation loop. The FLT3 mutants were found to adopt more stable configurations than the native enzyme. This was due to the different arrangements assumed by the JM domain. Larger fluctuations of the activation loop were found in four of the six mutants. In the native FLT3, the key residue Tyr(572) is involved in a strong and stable interaction with an ion pair. This interaction, which is thought to keep the JM in place hence regulating the activity of the enzyme, was found to break in all FLT3 mutants.

Place, publisher, year, edition, pages
Royal Society of Medicine Press, 2019
National Category
Theoretical Chemistry Physical Chemistry Biophysics
Research subject
Chemistry, Physical Chemistry
Identifiers
urn:nbn:se:lnu:diva-88817 (URN)10.1039/C9CP02938A (DOI)000483701200033 ()
Funder
Swedish Cancer Society, CAN 2015/387Swedish Cancer Society, CAN 2018/362Swedish National Infrastructure for Computing (SNIC), 2018/3-46Swedish National Infrastructure for Computing (SNIC), 2018/3-47Swedish National Infrastructure for Computing (SNIC), 2019/3-29
Available from: 2019-08-28 Created: 2019-08-28 Last updated: 2019-09-25Bibliographically approved
Georgoulia, P. S., Todde, G., Bjelic, S. & Friedman, R. (2019). The catalytic activity of Abl1 single and compound mutations: Implications for the mechanism of drug resistance mutations in chronic myeloid leukaemia. Biochimica et Biophysica Acta - General Subjects, 1863(4), 732-741
Open this publication in new window or tab >>The catalytic activity of Abl1 single and compound mutations: Implications for the mechanism of drug resistance mutations in chronic myeloid leukaemia
2019 (English)In: Biochimica et Biophysica Acta - General Subjects, ISSN 0304-4165, E-ISSN 1872-8006, Vol. 1863, no 4, p. 732-741Article in journal (Refereed) Published
Abstract [en]

Background

Abl1 is a protein tyrosine kinase whose aberrant activation due to mutations is the culprit of several cancers, most notably chronic myeloid leukaemia. Several Abl1 inhibitors are used as anti-cancer drugs. Unfortunately, drug resistance limits their effectiveness. The main cause for drug resistance is mutations in the kinase domain (KD) of Abl1 that evolve in patients. The T315I mutation confers resistance against all clinically-available inhibitors except ponatinib. Resistance to ponatinib can develop by compound (double) mutations.

Methods

Kinetic measurements of the KD of Abl1 and its mutants were carried out to examine their catalytic activity. Specifically, mutants that lead to drug resistance against ponatinib were considered. Molecular dynamics simulations and multiple sequence analysis were used for explanation of the experimental findings.

Results

The catalytic efficiency of the T315I pan-resistance mutant is more than two times lower than that of the native KD. All ponatinib resistant mutations restore the catalytic efficiency of the enzyme. Two of them (G250E/T315I and Y253H/E255V) have a catalytic efficiency that is more than five times that of the native KD.

Conclusions

The measurements and analysis suggest that resistance is at least partially due to the development of a highly efficient kinase through subsequent mutations. The simulations highlight modifications in two structurally important regions of Abl1, the activation and phosphate binding loops, upon mutations.

General significance

Experimental and computational methods were used together to explain how mutations in the kinase domain of Abl1 lead to resistance against the most advanced drug currently in use to treat chronic myeloid leukaemia.

Place, publisher, year, edition, pages
Elsevier, 2019
National Category
Biophysics Theoretical Chemistry Biochemistry and Molecular Biology
Research subject
Natural Science, Biomedical Sciences; Natural Science, Chemistry; Chemistry, Biochemistry
Identifiers
urn:nbn:se:lnu:diva-80308 (URN)10.1016/j.bbagen.2019.01.011 (DOI)000460853200009 ()30684523 (PubMedID)2-s2.0-85060896659 (Scopus ID)
Funder
Swedish Cancer Society, CAN 2015/387
Available from: 2019-02-07 Created: 2019-02-07 Last updated: 2019-08-29Bibliographically approved
Jha, S. K., Roth, M., Todde, G., Buchanan, J. P., Moser, R. D., Shukla, M. K. & Subramanian, G. (2018). Role of Stone-Wales defects or the interfacial interactions among graphene, carbon nanotubes, and Nylon 6: A first-principles study. Journal of Chemical Physics, 149(5), Article ID 054703.
Open this publication in new window or tab >>Role of Stone-Wales defects or the interfacial interactions among graphene, carbon nanotubes, and Nylon 6: A first-principles study
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2018 (English)In: Journal of Chemical Physics, ISSN 0021-9606, E-ISSN 1089-7690, Vol. 149, no 5, article id 054703Article in journal (Refereed) Published
Abstract [en]

We investigate computationally the role of Stone-Wales (SW) defects on the interfacial interactions among graphene, carbon nanotubes (CNTs), and Nylon 6 using density functional theory (DFT) and the empirical force-field. Our first-principles DFT calculations were performed using the Quantum ESPRESSO electronic structure code with the highly accurate van der Waals functional (vdW-DF2). Both pristine and SW-defected carbon nanomaterials were investigated. The computed results show that the presence of SW defects on CNTs weakens the CNT-graphene interactions. Our result that CNT-graphene interaction is much stronger than CNT-CNT interaction indicates that graphene would be able to promote the dispersion of CNTs in the polymer matrix. Our results demonstrate that carbon nanomaterials form stable complexes with Nylon 6 and that the van der Waals interactions, as revealed by the electronic charge density difference maps, play a key stabilizing role on the interfacial interactions among graphene, CNTs, and Nylon 6. Using the density of states calculations, we observed that the bandgaps of graphene and CNTs were not significantly modified due to their interactions with Nylon 6. The Young's moduli of complexes were found to be the averages of the moduli of their individual constituents. Published by AIP Publishing.

Place, publisher, year, edition, pages
American Institute of Physics (AIP), 2018
National Category
Materials Chemistry
Research subject
Natural Science, Chemistry
Identifiers
urn:nbn:se:lnu:diva-77493 (URN)10.1063/1.5032081 (DOI)000441008800023 ()30089374 (PubMedID)2-s2.0-85051117158 (Scopus ID)
Available from: 2018-08-31 Created: 2018-08-31 Last updated: 2019-08-29Bibliographically approved
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