SwePub
Sök i SwePub databas

  Utökad sökning

Träfflista för sökning "L773:0961 8368 OR L773:1469 896X ;lar1:(lnu)"

Sökning: L773:0961 8368 OR L773:1469 896X > Linnéuniversitetet

  • Resultat 1-3 av 3
Sortera/gruppera träfflistan
   
NumreringReferensOmslagsbildHitta
1.
  •  
2.
  • Maganhi, Stella Hernandez, et al. (författare)
  • Palbociclib can overcome mutations in cyclin dependent kinase 6 that break hydrogen bonds between the drug and the protein
  • 2017
  • Ingår i: Protein Science. - : Wiley-Blackwell. - 0961-8368 .- 1469-896X. ; 26:4, s. 870-879
  • Tidskriftsartikel (refereegranskat)abstract
    • Inhibition of cyclin dependent kinases (CDKs) 4 and 6 prevent cells from entering the synthesis phase of the cell cycle. CDK4 and 6 are therefore important drug targets in various cancers. The selective CDK4/6 inhibitor palbociclib is approved for the treatment of breast cancer and has shown activity in a cellular model of mixed lineage leukaemia (MLL)-rearranged acute myeloid leukaemia (AML). We studied the interactions of palbociclib and CDK6 using molecular dynamics simulations. Analysis of the simulations suggested several interactions that stabilized the drug in its binding site and that were not observed in the crystal structure of the protein-drug complex. These included a hydrogen bond to His 100 that was hitherto not reported and several hydrophobic contacts. Evolutionary-based bioinformatic analysis was used to suggest two mutants, D163G and H100L that would potentially yield drug resistance, as they lead to loss of important protein-drug interactions without hindering the viability of the protein. One of the mutants involved a change in the glycine of the well-conserved DFG motif of the kinase. Interestingly, CDK6-dependent human AML cells stably expressing either mutant retained sensitivity to palbociclib, indicating that the protein-drug interactions are not affected by these. Furthermore, the cells were proliferative in the absence of palbociclib, indicating that the Asp to Gly mutation in the DFG motif did not interfere with the catalytic activity of the protein.
  •  
3.
  • Otsuka, Felipe A. M., et al. (författare)
  • Evaluation of residue variability in a conformation-specific context and during evolutionary sequence reconstruction narrows drug resistance selection in Abl1 tyrosine kinase
  • 2022
  • Ingår i: Protein Science. - : John Wiley & Sons. - 0961-8368 .- 1469-896X. ; 31:7
  • Tidskriftsartikel (refereegranskat)abstract
    • Diseases with readily available therapies may eventually prevail against the specific treatment by the acquisition of resistance. The constitutively active Abl1 tyrosine kinase known to cause chronic myeloid leukemia is an example, where patients may experience relapse after small inhibitor drug treatment. Mutations in the Abl1 tyrosine kinase domain (Abl1-KD) are a critical source of resistance and their emergence depends on the conformational states that have been observed experimentally: the inactive state, the active state, and the intermediate inactive state that resembles Src kinase. Understanding how resistant positions and amino acid identities are determined by selection pressure during drug treatment is necessary to improve future drug development or treatment decisions. We carry out in silico site-saturation mutagenesis over the Abl1-KD structure in a conformational context to evaluate the in situ and conformational stability energy upon mutation. Out of the 11 studied resistant positions, we determined that 7 of the resistant mutations favored the active conformation of Abl1-KD with respect to the inactive state. When, instead, the sequence optimization was modeled simultaneously at resistant positions, we recovered five known resistant mutations in the active conformation. These results suggested that the Abl1 resistance mechanism targeted substitutions that favored the active conformation. Further sequence variability, explored by ancestral reconstruction in Abl1-KD, showed that neutral genetic drift, with respect to amino acid variability, was specifically diminished in the resistant positions. Since resistant mutations are susceptible to chance with a certain probability of fixation, combining methodologies outlined here may narrow and limit the available sequence space for resistance to emerge, resulting in more robust therapeutic treatments over time.
  •  
Skapa referenser, mejla, bekava och länka
  • Resultat 1-3 av 3

Kungliga biblioteket hanterar dina personuppgifter i enlighet med EU:s dataskyddsförordning (2018), GDPR. Läs mer om hur det funkar här.
Så här hanterar KB dina uppgifter vid användning av denna tjänst.

 
pil uppåt Stäng

Kopiera och spara länken för att återkomma till aktuell vy