A Microgravity Environment Improves Structural Resolution and Endows Cues for Specific Inhibition of Mitogen-Activated Protein Kinase Kinase 7

Abstract

Mitogen-activated protein kinase kinase 7 (MAP2K7) regulates stress and inflammatory responses, and is an attractive drug discovery target for serious diseases such as arthritis and cardiac hypertrophy. A microgravity environment improved the crystal quality of MAP2K7 and improved the structural resolution to 1.3 Å. High resolution analysis structurally clarified the two regions, which were undefined in the previous low-resolution analysis and conferred structural insights for producing MAP2K7-specific inhibitors. The hinge region alternatively configures the canonical and atypical conformations. The latter could allow binding MAP2K7 inhibitors with a novel scaffold. The C-terminal region works as a negative regulator with intermolecular association, which implies the ability to produce highly selective MAP2K7 inhibitors.