2 research outputs found
Molecular Recognition of PPARĪ³ by Kinase Cdk5/p25: Insights from a Combination of ProteināProtein Docking and Adaptive Biasing Force Simulations
The
peroxisome proliferator-activated receptor Ī³ (PPARĪ³)
is an important transcription factor that plays a major role in the
regulation of glucose and lipid metabolisms and has, therefore, many
implications in modern-life metabolic disorders such as diabetes,
obesity, and cardiovascular diseases. Phosphorylation of PPARĪ³
by the cyclin-dependent kinase 5 (Cdk5) has been recently proved to
promote obesity and loss of insulin sensitivity. The inhibition of
this reaction is currently being pursued to develop PPARĪ³ ligands
for type 2 diabetes treatments. The knowledge of the proteināprotein
interactions between Cdk5/p25 and PPARĪ³ can be an important
asset for better understanding of the molecular basis of the Cdk5-meditated
phosphorylation of PPARĪ³ and its inhibition. By means of a computational
approach that combines proteināprotein docking and adaptive
biasing force molecular dynamics simulations, we obtained PPARĪ³-Cdk5/p25
structural models that are consistent with the mechanism of the enzymatic
reaction and with overall structural features of the full length PPARĪ³-RXRĪ±
heterodimer bound to DNA. In addition to the active site, our model
shows that the interacting regions between the two proteins should
involve two distal docking sites, comprising the PPARĪ³ Ī©-loop
and Cdk5 N-terminal lobe and the PPARĪ³ Ī²-sheet and Cdk5
C-terminal lobe. These sites are related to PPARĪ³ transactivation
and directly interact with PPARĪ³ ligands. Our results suggest
that Ī²-sheets and Ī©-loop stabilization promoted by PPARĪ³
agonists could be important to inhibit Cdk5-mediated phosphorylation
DataSheet_1_Whole genome sequencing identifies novel mutations in malaria parasites resistant to artesunate (ATN) and to ATN + mefloquine combination.pdf
IntroductionThe global evolution of resistance to Artemisinin-based Combination Therapies (ACTs) by malaria parasites, will severely undermine our ability to control this devastating disease.MethodsHere, we have used whole genome sequencing to characterize the genetic variation in the experimentally evolved Plasmodium chabaudi parasite clone AS-ATNMF1, which is resistant to artesunate + mefloquine.Results and discussionFive novel single nucleotide polymorphisms (SNPs) were identified, one of which was a previously undescribed E738K mutation in a 26S proteasome subunit that was selected for under artesunate pressure (in AS-ATN) and retained in AS-ATNMF1. The wild type and mutated three-dimensional (3D) structure models and molecular dynamics simulations of the P. falciparum 26S proteasome subunit Rpn2 suggested that the E738K mutation could change the toroidal proteasome/cyclosome domain organization and change the recognition of ubiquitinated proteins. The mutation in the 26S proteasome subunit may therefore contribute to altering oxidation-dependent ubiquitination of the MDR-1 and/or K13 proteins and/or other targets, resulting in changes in protein turnover. In light of the alarming increase in resistance to artemisin derivatives and ACT partner drugs in natural parasite populations, our results shed new light on the biology of resistance and provide information on novel molecular markers of resistance that may be tested (and potentially validated) in the field.</p