Modeling conformational flexibility of kinases in inactive states

Abstract

Kinase structures in the inactive “DFG‐out” state provide a wealth of druggable binding site variants. The conformational plasticity of this state can be mainly described by different conformations of binding site‐forming elements such as DFG motif, A‐loop, P‐loop, and αC‐helix. Compared to DFG‐in structures, DFG‐out structures are largely underrepresented in the Protein Data Bank (PDB). Thus, structure‐based drug design efforts for DFG‐out inhibitors may benefit from an efficient approach to generate an ensemble of DFG‐out structures. Accordingly, the presented modeling pipeline systematically generates homology models of kinases in several DFG‐out conformations based on a sophisticated creation of template structures that represent the major states of the flexible structural elements. Eighteen template classes were initially selected from all available kinase structures in the PDB and subsequently employed for modeling the entire kinome in different DFG‐out variants by fusing individual structural elements to multiple chimeric template structures. Molecular dynamics simulations revealed that conformational transitions between the different DFG‐out states generally do not occur within trajectories of a few hundred nanoseconds length. This underlines the benefits of the presented homology modeling pipeline to generate relevant conformations of “DFG‐out” kinase structures for subsequent in silico screening or binding site analysis studies.

Molecular dynamics simulations of the conformational plasticity in the active pocket of salt-inducible kinase 2 (SIK2) multi-state binding with bosutinib

“…The conformation of the T -loop (open conformation) is similar among the protein kinases in the active state. However, the conformation of the T -loop for the inactive state of the protein kinase or the kinase with different inhibitors is diverse and flexible [ [15] , [16] , [109] ]. In particular, the conformation of the T -loop for ABL1 can be open or closed with different inhibitors, such as the closed conformation with imatinib (PDB ID: 2HYY [ 13 ]) and open conformation with axitinib (PDB ID: 4TWP [ 110 ]) ( Figure S66 ).…”

Deciphering the inhibition mechanism of a pseudokinase: integrin-bound kinase and cpd22

“…Para llevar a cabo las simulaciones de Dm la proteína se describió empleando el campo de fuerzas ff14sb (24), mientras que para el cPD22 se utilizó GAFF2 (25). Las cargas de este últimos se Figura 2.…”

Protein sequence‐to‐structure learning: Is this the end(‐to‐end revolution)?

“…Moreover, there is an imbalance in the PDB related to the abundance of pharmaceutically important proteins in complex with different ligands, or other factors. For example, the inactive state of kinases is largely underrepresented in the PDB compared to the active state [155]. This may bias datadriven approaches while, in principle, without any extrainformation about the context (post-translational modifications, bound ligand...etc), there is no reason why one state should be favoured over the other one.…”