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Determination and validation of mTOR kinase-domain 3D structure by homology modeling.

Lakhlili W, Chevé G, Yasri A, Ibrahimi A - Onco Targets Ther (2015)

Bottom Line: The quality and validation of the obtained model were performed using PROCHECK and PROVE softwares.The model validation was also done by docking of known inhibitors.In this paper, we describe and validate a 3D model for the mTOR catalytic site.

View Article: PubMed Central - PubMed

Affiliation: Laboratoire de Biotechnologie (MedBiotech), Faculté de Médecine et de Pharmacie de Rabat, Université Mohammed V de Rabat, Rabat, Morroco.

ABSTRACT
The AKT/mammalian target of rapamycin (mTOR) pathway is considered as one of the commonly activated and deregulated signaling pathways in human cancer. mTOR is associated with other proteins in two molecular complexes: mTOR complex 1/Raptor and the mTOR complex 2/Rictor. Using the crystal structure of the related lipid kinase PI3Kγ, we built a model of the catalytic region of mTOR. The modeling of the three-dimensional (3D) structure of the mTOR was performed by homology modeling program SWISS-MODEL. The quality and validation of the obtained model were performed using PROCHECK and PROVE softwares. The overall stereochemical property of the protein was assessed by the Ramachandran plot. The model validation was also done by docking of known inhibitors. In this paper, we describe and validate a 3D model for the mTOR catalytic site.

No MeSH data available.


Related in: MedlinePlus

Docking of known inhibitors into 3D model construction.Notes: Panel (A) shows the model built with a docked ligand superposed at the template 3L13 and its ligand. The model is in yellow, the PI3K (3L13) in blue, docked ligand (WYE) in red and the PI3K crystallized ligand (JZW) was in green. Panel (B) shows the superposition of the model of the ligand docked into catalytic site to ATP crystallized PI3K (PDB ID: 1E8X). The docked ligand (WYE) is in white, the ATP complexed into 1E8X in green, the BYM complexed into 2A4Z in Cyan.Abbreviations: PDB, Protein Data Bank; ATP, adenosine triphosphate.
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f7-ott-8-1923: Docking of known inhibitors into 3D model construction.Notes: Panel (A) shows the model built with a docked ligand superposed at the template 3L13 and its ligand. The model is in yellow, the PI3K (3L13) in blue, docked ligand (WYE) in red and the PI3K crystallized ligand (JZW) was in green. Panel (B) shows the superposition of the model of the ligand docked into catalytic site to ATP crystallized PI3K (PDB ID: 1E8X). The docked ligand (WYE) is in white, the ATP complexed into 1E8X in green, the BYM complexed into 2A4Z in Cyan.Abbreviations: PDB, Protein Data Bank; ATP, adenosine triphosphate.

Mentions: Following the construction and validation of our mTOR kinase-domain model, we employed pharmaceutical drug design approaches to virtually “dock” known mTOR kinase inhibitors into the putative ligand-binding pocket of the kinase domain. Figure 7A shows that the model with docked ligand (WYE) is perfectly superimposed on the template 3L13 with its ligand extracted from PDB.


Determination and validation of mTOR kinase-domain 3D structure by homology modeling.

Lakhlili W, Chevé G, Yasri A, Ibrahimi A - Onco Targets Ther (2015)

Docking of known inhibitors into 3D model construction.Notes: Panel (A) shows the model built with a docked ligand superposed at the template 3L13 and its ligand. The model is in yellow, the PI3K (3L13) in blue, docked ligand (WYE) in red and the PI3K crystallized ligand (JZW) was in green. Panel (B) shows the superposition of the model of the ligand docked into catalytic site to ATP crystallized PI3K (PDB ID: 1E8X). The docked ligand (WYE) is in white, the ATP complexed into 1E8X in green, the BYM complexed into 2A4Z in Cyan.Abbreviations: PDB, Protein Data Bank; ATP, adenosine triphosphate.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4525790&req=5

f7-ott-8-1923: Docking of known inhibitors into 3D model construction.Notes: Panel (A) shows the model built with a docked ligand superposed at the template 3L13 and its ligand. The model is in yellow, the PI3K (3L13) in blue, docked ligand (WYE) in red and the PI3K crystallized ligand (JZW) was in green. Panel (B) shows the superposition of the model of the ligand docked into catalytic site to ATP crystallized PI3K (PDB ID: 1E8X). The docked ligand (WYE) is in white, the ATP complexed into 1E8X in green, the BYM complexed into 2A4Z in Cyan.Abbreviations: PDB, Protein Data Bank; ATP, adenosine triphosphate.
Mentions: Following the construction and validation of our mTOR kinase-domain model, we employed pharmaceutical drug design approaches to virtually “dock” known mTOR kinase inhibitors into the putative ligand-binding pocket of the kinase domain. Figure 7A shows that the model with docked ligand (WYE) is perfectly superimposed on the template 3L13 with its ligand extracted from PDB.

Bottom Line: The quality and validation of the obtained model were performed using PROCHECK and PROVE softwares.The model validation was also done by docking of known inhibitors.In this paper, we describe and validate a 3D model for the mTOR catalytic site.

View Article: PubMed Central - PubMed

Affiliation: Laboratoire de Biotechnologie (MedBiotech), Faculté de Médecine et de Pharmacie de Rabat, Université Mohammed V de Rabat, Rabat, Morroco.

ABSTRACT
The AKT/mammalian target of rapamycin (mTOR) pathway is considered as one of the commonly activated and deregulated signaling pathways in human cancer. mTOR is associated with other proteins in two molecular complexes: mTOR complex 1/Raptor and the mTOR complex 2/Rictor. Using the crystal structure of the related lipid kinase PI3Kγ, we built a model of the catalytic region of mTOR. The modeling of the three-dimensional (3D) structure of the mTOR was performed by homology modeling program SWISS-MODEL. The quality and validation of the obtained model were performed using PROCHECK and PROVE softwares. The overall stereochemical property of the protein was assessed by the Ramachandran plot. The model validation was also done by docking of known inhibitors. In this paper, we describe and validate a 3D model for the mTOR catalytic site.

No MeSH data available.


Related in: MedlinePlus