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.
Highlights
Protein kinases are key players of cellular signal transduction.[1]
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 Protein Data Bank (PDB) and subsequently employed for modeling the entire kinome in different DFG-out variants by fusing individual structural elements to multiple chimeric template structures
Summary
Protein kinases are key players of cellular signal transduction.[1]. Since misregulation of kinases or mutations occur in several diseases, such as cancer and inflammation, human kinases comprise a large group of potential drug targets.[2]. The DFG-out conformation creates a hydrophobic pocket adjacent to the ATP binding site that can be targeted by the so-called type II inhibitors Another important structural element-determining catalytic activity is the position of the αC-helix, which consists of a conserved Glu residue and forms in the active state a crucial salt bridge with Lys of the N-lobe β3-strand but is usually moved outward in the inactive (DFG-out) state (Figure 1).[5,6]. The activation-loop remodeling method (ALRM) method[15] accounts for variability in the A-loop and an N-lobe rotation, while the DFGmodel approach[16] generates multiple models for a single kinase based on a selection of representative template structures considering mainly the relative positions of the N/C-lobes None of these three approaches considers the structural diversity of all structural elements characterizing inactive (“DFG-out”) structures. The presented homology modeling approach accounts for the flexibility of the inactive state of kinases and generates a representative subset of “DFG-out” conformations for binding site analysis or screening studies
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