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  • Ung et al examined a variety of structural

    2020-10-20

    Ung et al. examined a variety of structural features based upon the location of the DFG-motif and the αC-helix to define the conformational space of the catalytic domain of protein kinases [75]. They reported that the DFG motif can move from its active DFG-Din location to the inactive DFG-Dout location. Correspondingly, the αC-helix can move from its active αCin location to the inactive αCout position by rotating and tilting. These authors described five different protein kinase configurations; these include αCin-DFG-Din (CIDI), αCout-DGF-Din (CODI), αCin-DFG-Dout (CIDO), αCout-DFG-Dout (CODO), and ωCD; the latter designation signifies structures with variable locations of the αC-helix or DFG-D intermediate states. CIDI refers to the catalytically active conformation with a linear R-spine. In contrast, CIDO has the DFG-D motif 180° flip that reshapes the ATP-binding pocket and displaces DFG-F outward thereby breaking the R-spine. CODI signifies the αCout and DFG-Din conformation. This may result from the activation loop displacing the αC-helix to the αCout position. Alternatively, a drug may induce the outward movement of the αC-helix. The CODO conformation is rarely observed. ωCD structures are extremely heterogeneous with diverse DFG-D intermediate states and variable αC-helix positioning. Furthermore, Ung et al. suggest that ωCD structures may represent transition states among the various primary configurations [75].
    Drug-ligand binding pockets Liao [76] and van Linden et al. [77] divided the region between the protein kinase small and large lobes into the front cleft or front pocket, the gate area, and the back cleft. The gate area and back cleft make up the back pocket or molarity calculator pocket II (HPII) (Fig. 5). The front cleft includes the hinge residues, the adenine-binding pocket, the glycine-rich P-loop, and the catalytic loop (HRD(x)4N) residues. The gate area includes the β3-strand of the small lobe and the proximal section of the activation segment including DFG of the large lobe. The back-cleft extends to the αC-helix, the αC-β4 back loop, to portions of the β4- and β5-strands of the N-terminal lobe, and to a section of the αE-helix within the C-terminal lobe. One of the obstacles in the development of small molecule protein kinase inhibitors is to increase selectivity to reduce unwanted off-target side effects [78], a process that is aided by examining drug-kinase interactions [[79], [80], [81]]. van Linden et al. described several elements that are found in the front cleft, gate area, and back cleft [77]. For example, the front cleft contains an adenine-binding pocket (AP) along with two front pockets (FP-I and FP-II). FP-I is found between the solvent-exposed hinge residues and the large lobe xDFG-motif (where x is the amino acid immediately before the activation segment DFG) and FP-II is found between the glycine-rich P-loop and the β3-strand at the ceiling of the cleft in the small lobe. BP-I-A and BP-I-B occur in the gate area between the β3- and β4-strands, the conserved β3-strand K of the AxK signature, and the αC-helix of the small lobe and the xDFG-motif of the large lobe. The smaller BP-I-A is found at the top of the gate area and is enclosed by residues of the β3- and adjacent β5-strands including the β3-AxK residues and the regulatory αC-helix. The larger BP-I-B occurs in the center of the gate area allowing for access to the back cleft. Both BP-I-A and BP-I-B are found in both the DFG-Din and DFG-Dout conformations (Fig. 5). BP-II-A-in and BP-II-in occur within the back cleft of the DFG-Din conformation [76]. These sub-pockets are enclosed by the large lobe DFG-motif and the small lobe αC-helix, αC-β4 back loop, and the β4- and β5-strands. Major changes of BP-II-A-in and BP-II-in produce BP-II-out that is found in the DFG-Dout configuration; this structural transformation occurs with the movement of DFG-F. The resulting region is called back pocket II-out (BP-II-out); it is found where the DFG-F is located in the DFG-Din configuration. BP-II-B is enclosed by the αC-helix and the adjacent β4-strand in both the DFG-Din and DFG-Dout conformations. Back pocket III (BP-III) is observed only in the DFG-Dout conformation. This region is found on the floor of BP-II-out between the β6-strand, the conserved catalytic loop HRD-H, the activation segment DFG-Dout motif, and the αE-helices of the large lobe along with the αC-β4 back loop and the αC-helix of the small lobe. Two pockets that are partially solvent exposed (BP-IV and BP-V) occur between the small lobe αC-helix and the large lobe DFG-Dout motif, the catalytic loop, the β6-strand, and the activation segment (Fig. 5).