Structural insight into maternal embryonic leucine zipper kinase (MELK) Conformation and inhibition toward structure-based drug design

Giulia Canevari; Stefania Re Depaolini; Ulisse Cucchi; Jay A. Bertrand; Elena Casale; Claudia Perrera; Barbara Forte; Patrizia Carpinelli; Eduard R. Felder

doi:10.1021/bi4005864

Structural insight into maternal embryonic leucine zipper kinase (MELK) Conformation and inhibition toward structure-based drug design

Giulia Canevari (Lead / Corresponding author), Stefania Re Depaolini, Ulisse Cucchi, Jay A. Bertrand, Elena Casale, Claudia Perrera, Barbara Forte, Patrizia Carpinelli, Eduard R. Felder

Drug Discovery Unit

Research output: Contribution to journal › Article › peer-review

31 Citations (Scopus)

Abstract

Maternal embryonic leucine zipper kinase (MELK) is upregulated in several types of tumor, including breast, prostate, and brain tumors. Its expression is generally associated with cell survival, cell proliferation, and resistance to apoptosis. Therefore, the potential of MELK inhibitors as therapeutic agents is recently attracting considerable interest. Here we report the first structures of MELK in complex with AMP-PNP and with nanomolar inhibitors. Our studies shed light on the role of the MELK UBA domain, provide a characterization of the kinase active site, and identify key residues for achieving high potency, laying the groundwork for structure-based drug design efforts.

Original language	English
Pages (from-to)	6380-6387
Number of pages	8
Journal	Biochemistry
Volume	52
Issue number	37
Early online date	5 Aug 2013
DOIs	https://doi.org/10.1021/bi4005864
Publication status	Published - 17 Sept 2013

Keywords

Cancer
Cells
Conformation
Drug discovery
Peptides and proteins

ASJC Scopus subject areas

Biochemistry

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1021/bi4005864

Cite this

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title = "Structural insight into maternal embryonic leucine zipper kinase (MELK) Conformation and inhibition toward structure-based drug design",

abstract = "Maternal embryonic leucine zipper kinase (MELK) is upregulated in several types of tumor, including breast, prostate, and brain tumors. Its expression is generally associated with cell survival, cell proliferation, and resistance to apoptosis. Therefore, the potential of MELK inhibitors as therapeutic agents is recently attracting considerable interest. Here we report the first structures of MELK in complex with AMP-PNP and with nanomolar inhibitors. Our studies shed light on the role of the MELK UBA domain, provide a characterization of the kinase active site, and identify key residues for achieving high potency, laying the groundwork for structure-based drug design efforts.",

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T1 - Structural insight into maternal embryonic leucine zipper kinase (MELK) Conformation and inhibition toward structure-based drug design

AU - Canevari, Giulia

AU - Re Depaolini, Stefania

AU - Cucchi, Ulisse

AU - Bertrand, Jay A.

AU - Casale, Elena

AU - Perrera, Claudia

AU - Forte, Barbara

AU - Carpinelli, Patrizia

AU - Felder, Eduard R.

PY - 2013/9/17

Y1 - 2013/9/17

N2 - Maternal embryonic leucine zipper kinase (MELK) is upregulated in several types of tumor, including breast, prostate, and brain tumors. Its expression is generally associated with cell survival, cell proliferation, and resistance to apoptosis. Therefore, the potential of MELK inhibitors as therapeutic agents is recently attracting considerable interest. Here we report the first structures of MELK in complex with AMP-PNP and with nanomolar inhibitors. Our studies shed light on the role of the MELK UBA domain, provide a characterization of the kinase active site, and identify key residues for achieving high potency, laying the groundwork for structure-based drug design efforts.

AB - Maternal embryonic leucine zipper kinase (MELK) is upregulated in several types of tumor, including breast, prostate, and brain tumors. Its expression is generally associated with cell survival, cell proliferation, and resistance to apoptosis. Therefore, the potential of MELK inhibitors as therapeutic agents is recently attracting considerable interest. Here we report the first structures of MELK in complex with AMP-PNP and with nanomolar inhibitors. Our studies shed light on the role of the MELK UBA domain, provide a characterization of the kinase active site, and identify key residues for achieving high potency, laying the groundwork for structure-based drug design efforts.

KW - Cancer

KW - Cells

KW - Conformation

KW - Drug discovery

KW - Peptides and proteins

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Structural insight into maternal embryonic leucine zipper kinase (MELK) Conformation and inhibition toward structure-based drug design

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

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