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Predicting inactive conformations of protein kinases using active structures: conformational selection of type-II inhibitors.

ABSTRACT: Protein kinases have been found to possess two characteristic conformations in their activation-loops: the active DFG-in conformation and the inactive DFG-out conformation. Recently, it has been very interesting to develop type-II inhibitors which target the DFG-out conformation and are more specific than the type-I inhibitors binding to the active DFG-in conformation. However, solving crystal structures of kinases with the DFG-out conformation remains a challenge, and this seriously hampers the application of the structure-based approaches in development of novel type-II inhibitors. To overcome this limitation, here we present a computational approach for predicting the DFG-out inactive conformation using the DFG-in active structures, and develop related conformational selection protocols for the uses of the predicted DFG-out models in the binding pose prediction and virtual screening of type-II ligands. With the DFG-out models, we predicted the binding poses for known type-II inhibitors, and the results were found in good agreement with the X-ray crystal structures. We also tested the abilities of the DFG-out models to recognize their specific type-II inhibitors by screening a database of small molecules. The AUC (area under curve) results indicated that the predicted DFG-out models were selective toward their specific type-II inhibitors. Therefore, the computational approach and protocols presented in this study are very promising for the structure-based design and screening of novel type-II kinase inhibitors.

SUBMITTER: Xu M

PROVIDER: S-EPMC3144914 | biostudies-literature | 2011

REPOSITORIES: biostudies-literature

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Predicting inactive conformations of protein kinases using active structures: conformational selection of type-II inhibitors.

Xu Min M Yu Lu L Wan Bo B Yu Long L Huang Qiang Q

PloS one 20110727 7

Protein kinases have been found to possess two characteristic conformations in their activation-loops: the active DFG-in conformation and the inactive DFG-out conformation. Recently, it has been very interesting to develop type-II inhibitors which target the DFG-out conformation and are more specific than the type-I inhibitors binding to the active DFG-in conformation. However, solving crystal structures of kinases with the DFG-out conformation remains a challenge, and this seriously hampers the ...[more]

PMID: 21818358

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Project description:BackgroundKinases are a family of enzymes that catalyze the transfer of the ɤ-phosphate group from ATP to a protein's residue. Malfunctioning kinases are involved in many health problems such as cardiovascular diseases, diabetes, and cancer. Kinases transitions between multiple conformations of inactive to active forms attracted considerable interest.MethodA reaction coordinate is computed for the transition between the active to inactive conformation in Abl kinase with a focus on the DFG-in to DFG-out flip. The method of Rock Climbing is used to construct a path locally, which is subsequently optimized using a functional of the entire path. The discrete coordinate sets along the reaction path are used in a Milestoning calculation of the free energy landscape and the rate of the transition.ResultsThe estimated transition times are between a few milliseconds and seconds, consistent with simulations of the kinetics and with indirect experimental data. The activation requires the transient dissociation of the salt bridge between Lys271 and Glu286. The salt bridge reforms once the DFG motif is stabilized by a locked conformation of Phe382. About ten residues are identified that contribute significantly to the process and are included as part of the reaction space.ConclusionsThe transition from DFG-in to DFG-out in Abl kinase was simulated using atomic resolution of a fully solvated protein yielding detailed description of the kinetics and the mechanism of the DFG flip. The results are consistent with other computational methods that simulate the kinetics and with some indirect experimental measurements.General significanceThe activation of kinases includes a conformational transition of the DFG motif that is important for enzyme activity but is not accessible to conventional Molecular Dynamics. We propose a detailed mechanism for the transition, at a timescale longer than conventional MD, using a combination of reaction path and Milestoning algorithms. The mechanism includes local structural adjustments near the binding site as well as collective interactions with more remote residues.

Dataset Information

Predicting inactive conformations of protein kinases using active structures: conformational selection of type-II inhibitors.

Publications

Predicting inactive conformations of protein kinases using active structures: conformational selection of type-II inhibitors.

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