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Evolutionary sequence and structural basis for the distinct conformational landscapes of Tyr and Ser/Thr kinases.
- Source :
-
Nature communications [Nat Commun] 2024 Aug 02; Vol. 15 (1), pp. 6545. Date of Electronic Publication: 2024 Aug 02. - Publication Year :
- 2024
-
Abstract
- Protein kinases are molecular machines with rich sequence variation that distinguishes the two main evolutionary branches - tyrosine kinases (TKs) from serine/threonine kinases (STKs). Using a sequence co-variation Potts statistical energy model we previously concluded that TK catalytic domains are more likely than STKs to adopt an inactive conformation with the activation loop in an autoinhibitory folded conformation, due to intrinsic sequence effects. Here we investigate the structural basis for this phenomenon by integrating the sequence-based model with structure-based molecular dynamics (MD) to determine the effects of mutations on the free energy difference between active and inactive conformations, using a thermodynamic cycle involving many (nā=ā108) protein-mutation free energy perturbation (FEP) simulations in the active and inactive conformations. The sequence and structure-based results are consistent and support the hypothesis that the inactive conformation DFG-out Activation Loop Folded, is a functional regulatory state that has been stabilized in TKs relative to STKs over the course of their evolution via the accumulation of residue substitutions in the activation loop and catalytic loop that facilitate distinct substrate binding modes in trans and additional modes of regulation in cis for TKs.<br /> (© 2024. The Author(s).)
- Subjects :
- Protein Conformation
Thermodynamics
Mutation
Amino Acid Sequence
Humans
Molecular Dynamics Simulation
Catalytic Domain
Protein-Tyrosine Kinases chemistry
Protein-Tyrosine Kinases genetics
Protein-Tyrosine Kinases metabolism
Evolution, Molecular
Protein Serine-Threonine Kinases chemistry
Protein Serine-Threonine Kinases genetics
Protein Serine-Threonine Kinases metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 2041-1723
- Volume :
- 15
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Nature communications
- Publication Type :
- Academic Journal
- Accession number :
- 39095350
- Full Text :
- https://doi.org/10.1038/s41467-024-50812-0