2HW6

Crystal structure of Mnk1 catalytic domain

Summary for 2HW6

• Entry DOI: 10.2210/pdb2hw6/pdb
• Related: 2AC3 2AC5 2HW7
• Descriptor: MAP kinase-interacting serine/threonine-protein kinase 1, SULFATE ION (3 entities in total)
• Functional Keywords: protein kinase, drug design, mnk1, phosphorylation, transferase
• Biological source: Homo sapiens (human)
• Cellular location: Isoform 2: Cytoplasm. Isoform 3: Cytoplasm: Q9BUB5
• Total number of polymer chains: 2
• Total formula weight: 69148.41

Authors

Jauch, R.,Wahl, M.C. (deposition date: 2006-08-01, release date: 2006-08-29, Last modification date: 2023-08-30)

Primary citation

Jauch, R.,Cho, M.K.,Netter, C.,Schreiter, K.,Aicher, B.,Zweckstetter, M.,Wahl, M.C.
Mitogen-activated protein kinases interacting kinases are autoinhibited by a reprogrammed activation segment.
Embo J., 25:4020-4032, 2006

PubMed Abstract: Autoinhibition is a recurring mode of protein kinase regulation and can be based on diverse molecular mechanisms. Here, we show by crystal structure analysis, nuclear magnetic resonance (NMR)-based nucleotide affinity studies and rational mutagenesis that nonphosphorylated mitogen-activated protein (MAP) kinases interacting kinase (Mnk) 1 is autoinhibited by conversion of the activation segment into an autoinhibitory module. In a Mnk1 crystal structure, the activation segment is repositioned via a Mnk-specific sequence insertion at the N-terminal lobe with the following consequences: (i) the peptide substrate binding site is deconstructed, (ii) the interlobal cleft is narrowed, (iii) an essential Lys-Glu pair is disrupted and (iv) the magnesium-binding loop is locked into an ATP-competitive conformation. Consistently, deletion of the Mnk-specific insertion or removal of a conserved phenylalanine side chain, which induces a blockade of the ATP pocket, increase the ATP affinity of Mnk1. Structural rearrangements required for the activation of Mnks are apparent from the cocrystal structure of a Mnk2 D228G -staurosporine complex and can be modeled on the basis of crystal packing interactions. Our data suggest a novel regulatory mechanism specific for the Mnk subfamily.

PubMed: 16917500
DOI: 10.1038/sj.emboj.7601285

Experimental method

X-RAY DIFFRACTION (2.5 Å)