The DFG motif at the beginning of the activation loop of the MAPK p38a undergoes a local structural reorganizationupon binding of allosteric type-II and type-III inhibitors, which causes the residue F169 to movefrom a buried conformation (defined as DFG-in) to a solvent exposed conformation (defined as DFG-out).Although both experimental and computer simulation studies had been performed with the aim ofunveiling the details of the DFG-in to DFG-out transition, the molecular mechanism is still far from beingunequivocally depicted.Here, the accelerated molecular dynamics (AMD) technique has been applied to model the active loopflexibility of p38a and sample special protein conformations which can be accessible only in some conditionsor time periods. Starting from the assumption of an experimentally known initial and final state ofthe protein, the study allowed the description of the interaction network and the structural intermediateswhich lead the protein to change its loop conformation and active site accessibility. Besides a few importanthydrogen bond interactions, a primary role seems to be played by cation–p interactions, involvingthe DFG-loop residue F169, which participate in the stabilization of an intermediate conformation andin its consequent transition to the DFG-out conformation. From this study, insights which may prove usefulfor inhibitor design and/or site directed mutagenesis studies are derived.

Insight into MAPK P38α DFG-Flip mechanism by accelerated molecular dynamics / Filomia, Federico; De Rienzo, Francesca; Menziani, Maria Cristina. - In: BIOORGANIC & MEDICINAL CHEMISTRY. - ISSN 0968-0896. - STAMPA. - 18:(2010), pp. 6505-6512. [10.1016/j.bmc.2010.07.047]

Insight into MAPK P38α DFG-Flip mechanism by accelerated molecular dynamics

FILOMIA, Federico;DE RIENZO, Francesca;MENZIANI, Maria Cristina
2010

Abstract

The DFG motif at the beginning of the activation loop of the MAPK p38a undergoes a local structural reorganizationupon binding of allosteric type-II and type-III inhibitors, which causes the residue F169 to movefrom a buried conformation (defined as DFG-in) to a solvent exposed conformation (defined as DFG-out).Although both experimental and computer simulation studies had been performed with the aim ofunveiling the details of the DFG-in to DFG-out transition, the molecular mechanism is still far from beingunequivocally depicted.Here, the accelerated molecular dynamics (AMD) technique has been applied to model the active loopflexibility of p38a and sample special protein conformations which can be accessible only in some conditionsor time periods. Starting from the assumption of an experimentally known initial and final state ofthe protein, the study allowed the description of the interaction network and the structural intermediateswhich lead the protein to change its loop conformation and active site accessibility. Besides a few importanthydrogen bond interactions, a primary role seems to be played by cation–p interactions, involvingthe DFG-loop residue F169, which participate in the stabilization of an intermediate conformation andin its consequent transition to the DFG-out conformation. From this study, insights which may prove usefulfor inhibitor design and/or site directed mutagenesis studies are derived.
18
6505
6512
Insight into MAPK P38α DFG-Flip mechanism by accelerated molecular dynamics / Filomia, Federico; De Rienzo, Francesca; Menziani, Maria Cristina. - In: BIOORGANIC & MEDICINAL CHEMISTRY. - ISSN 0968-0896. - STAMPA. - 18:(2010), pp. 6505-6512. [10.1016/j.bmc.2010.07.047]
Filomia, Federico; DE RIENZO, Francesca; Menziani, Maria Cristina
File in questo prodotto:
Non ci sono file associati a questo prodotto.
Pubblicazioni consigliate

Caricamento pubblicazioni consigliate

Licenza Creative Commons
I metadati presenti in IRIS UNIMORE sono rilasciati con licenza Creative Commons CC0 1.0 Universal, mentre i file delle pubblicazioni sono rilasciati con licenza Attribuzione 4.0 Internazionale (CC BY 4.0), salvo diversa indicazione.
In caso di violazione di copyright, contattare Supporto Iris

Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11380/645259
Citazioni
  • ???jsp.display-item.citation.pmc??? 12
  • Scopus 35
  • ???jsp.display-item.citation.isi??? 35
social impact