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PLoS One. 2013 Jul 26;8(7):e70031. doi: 10.1371/journal.pone.0070031. Print 2013.

Structural basis for the regulation of maternal embryonic leucine zipper kinase.

Author information

1
MOE Key Laboratory of Protein Sciences and Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing, China.

Abstract

MELK (maternal embryonic leucine zipper kinase), which is a member of the AMPK (AMP-activated protein kinase)-related kinase family, plays important roles in diverse cellular processes and has become a promising drug target for certain cancers. However, the regulatory mechanism of MELK remains elusive. Here, we report the crystal structure of a fragment of human MELK that contains the kinase domain and ubiquitin-associated (UBA) domain. The UBA domain tightly binds to the back of the kinase domain, which may contribute to the proper conformation and activity of the kinase domain. Interestingly, the activation segment in the kinase domain displays a unique conformation that contains an intramolecular disulfide bond. The structural and biochemical analyses unravel the molecular mechanisms for the autophosphorylation/activation of MELK and the dependence of its catalytic activity on reducing agents. Thus, our results may provide the basis for designing specific MELK inhibitors for cancer treatment.

PMID:
23922895
PMCID:
PMC3724675
DOI:
10.1371/journal.pone.0070031
[Indexed for MEDLINE]
Free PMC Article

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