4i5h
From Proteopedia
Crystal Structure of a Double Mutant Rat Erk2 Complexed With a Type II Quinazoline Inhibitor
Structural highlights
FunctionMK01_RAT Serine/threonine kinase which acts as an essential component of the MAP kinase signal transduction pathway. MAPK1/ERK2 and MAPK3/ERK1 are the 2 MAPKs which play an important role in the MAPK/ERK cascade. They participate also in a signaling cascade initiated by activated KIT and KITLG/SCF. Depending on the cellular context, the MAPK/ERK cascade mediates diverse biological functions such as cell growth, adhesion, survival and differentiation through the regulation of transcription, translation, cytoskeletal rearrangements. The MAPK/ERK cascade plays also a role in initiation and regulation of meiosis, mitosis, and postmitotic functions in differentiated cells by phosphorylating a number of transcription factors. About 160 substrates have already been discovered for ERKs. Many of these substrates are localized in the nucleus, and seem to participate in the regulation of transcription upon stimulation. However, other substrates are found in the cytosol as well as in other cellular organelles, and those are responsible for processes such as translation, mitosis and apoptosis. Moreover, the MAPK/ERK cascade is also involved in the regulation of the endosomal dynamics, including lysosome processing and endosome cycling through the perinuclear recycling compartment (PNRC); as well as in the fragmentation of the Golgi apparatus during mitosis. The substrates include transcription factors (such as ATF2, BCL6, ELK1, ERF, FOS, HSF4 or SPZ1), cytoskeletal elements (such as CANX, CTTN, GJA1, MAP2, MAPT, PXN, SORBS3 or STMN1), regulators of apoptosis (such as BAD, BTG2, CASP9, DAPK1, IER3, MCL1 or PPARG), regulators of translation (such as EIF4EBP1) and a variety of other signaling-related molecules (like ARHGEF2, DCC, FRS2 or GRB10). Protein kinases (such as RAF1, RPS6KA1/RSK1, RPS6KA3/RSK2, RPS6KA2/RSK3, RPS6KA6/RSK4, SYK, MKNK1/MNK1, MKNK2/MNK2, RPS6KA5/MSK1, RPS6KA4/MSK2, MAPKAPK3 or MAPKAPK5) and phosphatases (such as DUSP1, DUSP4, DUSP6 or DUSP16) are other substrates which enable the propagation the MAPK/ERK signal to additional cytosolic and nuclear targets, thereby extending the specificity of the cascade. May play a role in the spindle assembly checkpoint.[1] Acts as a transcriptional repressor. Binds to a [GC]AAA[GC] consensus sequence. Repress the expression of interferon gamma-induced genes. Seems to bind to the promoter of CCL5, DMP1, IFIH1, IFITM1, IRF7, IRF9, LAMP3, OAS1, OAS2, OAS3 and STAT1. Transcriptional activity is independent of kinase activity (By similarity).[2] Publication Abstract from PubMedOnly a small percentage of protein kinases have been shown to adopt a distinct inactive ATP-binding site conformation, called the Asp-Phe-Gly-out (DFG-out) conformation. Given the high degree of homology within this enzyme family, we sought to understand the basis of this disparity on a sequence level. We identified two residue positions that sensitize mitogen-activated protein kinases (MAPKs) to inhibitors that stabilize the DFG-out inactive conformation. After characterizing the structure and dynamics of an inhibitor-sensitive MAPK mutant, we demonstrated the generality of this strategy by sensitizing a kinase (apoptosis signal-regulating kinase 1) not in the MAPK family to several DFG-out stabilizing ligands, using the same residue positions. The use of specific inactive conformations may aid the study of noncatalytic roles of protein kinases, such as binding partner interactions and scaffolding effects. Sequence determinants of a specific inactive protein kinase conformation.,Hari SB, Merritt EA, Maly DJ Chem Biol. 2013 Jun 20;20(6):806-15. doi: 10.1016/j.chembiol.2013.05.005. PMID:23790491[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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