4BKY

Crystal structure of unphosphorylated Maternal Embryonic Leucine zipper Kinase (MELK) in complex with pyrrolopyrazole inhibitor

Summary for 4BKY

• Entry DOI: 10.2210/pdb4bky/pdb
• Related: 4BKZ 4BL1
• Descriptor: MATERNAL EMBRYONIC LEUCINE ZIPPER KINASE, 3'-{[(4-bromo-1-methyl-1H-pyrrol-2-yl)carbonyl]amino}-N-[(1S)-1-phenyl-2-(pyrrolidin-1-yl)ethyl]-1',4'-dihydro-5'H-spiro[cyclopropane-1,6'-pyrrolo[3,4-c]pyrazole]-5'-carboxamide, UNKNOWN ATOM OR ION, ... (4 entities in total)
• Functional Keywords: transferase
• Biological source: HOMO SAPIENS (HUMAN)
• Total number of polymer chains: 1
• Total formula weight: 40773.00

Authors

Canevari, G.,Re Depaolini, S.,Cucchi, U.,Forte, B.,Carpinelli, P.,Bertrand, J.A. (deposition date: 2013-04-30, release date: 2013-08-21, Last modification date: 2023-12-20)

Primary citation

Canevari, G.,Re Depaolini, S.,Cucchi, U.,Bertrand, J.A.,Casale, E.,Perrera, C.,Forte, B.,Carpinelli, P.,Felder, E.R.
Structural Insight Into Maternal Embryonic Leucine Zipper Kinase (Melk) Conformation and Inhibition Towards Structure- Based Drug Design.
Biochemistry, 52:6380-, 2013

PubMed 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.

PubMed: 23914841
DOI: 10.1021/BI4005864

Experimental method

X-RAY DIFFRACTION (1.83 Å)