Talin-driven inside-out activation mechanism of platelet αIIbβ3 integrin probed by multimicrosecond, all-atom molecular dynamics simulations

Chiglitazar is a promising new-generation insulin sensitizer with low reverse effects for the treatment of type II diabetes mellitus (T2DM) and has shown activity as a nonselective pan-agonist to the human peroxisome proliferator-activated receptors (PPARs) (i.e., full activation of PPARγ and a partial activation of PPARα and PPARβ/δ). Yet, it has no high-resolution complex structure with PPARs and its detailed interactions and activation mechanism remain unclear. In this study, we docked chiglitazar into three experimentally resolved crystal structures of hPPAR subtypes, PPARα, PPARβ/δ, and PPARγ, followed by 3 μs molecular dynamics simulations for each system. Our MM-GBSA binding energy calculation revealed that chiglitazar most favorably bound to hPPARγ (-144.6 kcal/mol), followed by hPPARα (-138.0 kcal/mol) and hPPARβ (-135.9 kcal/mol), and the order is consistent with the experimental data. Through the decomposition of the MM-GBSA binding energy by residue and the use of two-dimensional interaction diagrams, key residues involved in the binding of chiglitazar were identified and characterized for each complex system. Additionally, our detailed dynamics analyses support that the conformation and dynamics of helix 12 play a critical role in determining the activities of the different types of ligands (e.g., full agonist vs. partial agonist). Rather than being bent fully in the direction of the agonist versus antagonist conformation, a partial agonist can adopt a more linear conformation and have a lower degree of flexibility. Our finding may aid in further development of this new generation of medication.

Download Full-text

1Q1324 Activation mechanism of rhodopsin elucidated by molecular dynamics simulations(Photobiology: Vision & Photoreception 1,The 49th Annual Meeting of the Biophysical Society of Japan)

Seibutsu Butsuri ◽

10.2142/biophys.51.s69_3 ◽

2011 ◽

Vol 51 (supplement) ◽

pp. S69

Author(s):

Fuyuki Sakai ◽

Shoji Takada

Keyword(s):

Molecular Dynamics ◽

Molecular Dynamics Simulations ◽

Annual Meeting ◽

Activation Mechanism ◽

Biophysical Society ◽

Dynamics Simulations

Download Full-text

Mechanistic Insights into αIIbβ3 Integrin Signaling from Long-Timescale Molecular Dynamics Simulations

Biophysical Journal ◽

10.1016/j.bpj.2011.11.2177 ◽

2012 ◽

Vol 102 (3) ◽

pp. 398a-399a

Author(s):

Davide Provasi ◽

Ana Negri ◽

Barry Coller ◽

Marta Filizola

Keyword(s):

Molecular Dynamics ◽

Molecular Dynamics Simulations ◽

Integrin Signaling ◽

Dynamics Simulations ◽

Αiibβ3 Integrin

Download Full-text

Changes in the free-energy landscape of p38α MAP kinase through its canonical activation and binding events as studied by enhanced molecular dynamics simulations

eLife ◽

10.7554/elife.22175 ◽

2017 ◽

Vol 6 ◽

Cited By ~ 23

Author(s):

Antonija Kuzmanic ◽

Ludovico Sutto ◽

Giorgio Saladino ◽

Angel R Nebreda ◽

Francesco L Gervasio ◽

...

Keyword(s):

Molecular Dynamics ◽

Molecular Dynamics Simulations ◽

Molecular Mechanism ◽

Fine Tuning ◽

Activation Mechanism ◽

Cellular Processes ◽

Dynamics Simulations ◽

P38α Kinase ◽

P38α Map Kinase ◽

First Time

p38α is a Ser/Thr protein kinase involved in a variety of cellular processes and pathological conditions, which makes it a promising pharmacological target. Although the activity of the enzyme is highly regulated, its molecular mechanism of activation remains largely unexplained, even after decades of research. By using state-of-the-art molecular dynamics simulations, we decipher the key elements of the complex molecular mechanism refined by evolution to allow for a fine tuning of p38α kinase activity. Our study describes for the first time the molecular effects of different regulators of the enzymatic activity, and provides an integrative picture of the activation mechanism that explains the seemingly contradictory X-ray and NMR data.

Download Full-text

Development of IKATP Ion Channel Blockers Targeting Sulfonylurea Resistant Mutant KIR6.2 Based Channels for Treating DEND Syndrome

Frontiers in Pharmacology ◽

10.3389/fphar.2021.814066 ◽

2022 ◽

Vol 12 ◽

Author(s):

Marien J. C. Houtman ◽

Theres Friesacher ◽

Xingyu Chen ◽

Eva-Maria Zangerl-Plessl ◽

Marcel A. G. van der Heyden ◽

...

Keyword(s):

Molecular Dynamics ◽

Patch Clamp ◽

Molecular Dynamics Simulations ◽

Drug Binding ◽

Channel Blockers ◽

Drug Candidates ◽

Channel Inhibition ◽

Patch Clamp Electrophysiology ◽

Dynamics Simulations ◽

Inside Out

Introduction: DEND syndrome is a rare channelopathy characterized by a combination of developmental delay, epilepsy and severe neonatal diabetes. Gain of function mutations in the KCNJ11 gene, encoding the KIR6.2 subunit of the IKATP potassium channel, stand at the basis of most forms of DEND syndrome. In a previous search for existing drugs with the potential of targeting Cantú Syndrome, also resulting from increased IKATP, we found a set of candidate drugs that may also possess the potential to target DEND syndrome. In the current work, we combined Molecular Modelling including Molecular Dynamics simulations, with single cell patch clamp electrophysiology, in order to test the effect of selected drug candidates on the KIR6.2 WT and DEND mutant channels.Methods: Molecular dynamics simulations were performed to investigate potential drug binding sites. To conduct in vitro studies, KIR6.2 Q52R and L164P mutants were constructed. Inside/out patch clamp electrophysiology on transiently transfected HEK293T cells was performed for establishing drug-channel inhibition relationships.Results: Molecular Dynamics simulations provided insight in potential channel interaction and shed light on possible mechanisms of action of the tested drug candidates. Effective IKIR6.2/SUR2a inhibition was obtained with the pore-blocker betaxolol (IC50 values 27–37 μM). Levobetaxolol effectively inhibited WT and L164P (IC50 values 22 μM) and Q52R (IC50 55 μM) channels. Of the SUR binding prostaglandin series, travoprost was found to be the best blocker of WT and L164P channels (IC50 2–3 μM), while Q52R inhibition was 15–20% at 10 μM.Conclusion: Our combination of MD and inside-out electrophysiology provides the rationale for drug mediated IKATP inhibition, and will be the basis for 1) screening of additional existing drugs for repurposing to address DEND syndrome, and 2) rationalized medicinal chemistry to improve IKATP inhibitor efficacy and specificity.

Download Full-text