The MAP kinases, ERK1/2, are the terminal enzymes in the oncogenic RAS-RAF signaling pathway. Inhibitors targeting upstream enzymes have achieved dramatic clinical success for metastatic melanoma, but most patients develop resistance. Because of this, ERKs are emerging targets for therapeutics, and high-affinity inhibitors are in early-stage clinical trials. Therefore, understanding regulatory mechanisms for ERKs is a timely and important goal.  

X-ray crystallography structures for the inactive vs phosphorylated states show only very small changes in the active site. Key observations from HX-MS and NMR experiments regarding the dynamic behavior of the activation loop are not evident from the crystal structures alone (1). Recent temperature-dependent HX-MS experiments are providing further evidence of the dynamic nature of ERK2. 

Molecular dynamics simulations have the potential to provide insights into the conformational space and electrostatics driving forces for the ERK2 enzyme in various states (2). In addition, multiscale hybrid quantum mechanics and molecular mechanics (QM/MM) potentials can be used to explore the atomistic details of the catalyzed phosphoryl transfer from ATP. This work will be carried out as a collaboration between the NIST Thermodynamics Research group and the Ahn lab at CU-Boulder. 

   

1. Pegram LM, Liddle JC, Xiao Y, Hoh M, Rudolph J, Iverson DB, Vigers GP, Smith D, Zhang H, Wang W, Moffat JG,  Activation loop dynamics are controlled by conformation-selective inhibitors of ERK2, PNAS, 2019 (DOI: 10.1073/pnas.1906824116)

2. Tsai CC, Yue Z, Shen J, How electrostatic coupling enables conformational plasticity in a tyrosine kinase, JACS, 2019 (DOI: 10.1021/jacs.9b06064)

key words

Molecular dynamics; Electrostatics; Drug Design; Enzyme; Kinase; Allostery; Cancer

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Level:  Open to Postdoctoral applicants