4UMT

Structure of MELK in complex with inhibitors

Summary for 4UMT

• Entry DOI: 10.2210/pdb4umt/pdb
• Related: 4UMP 4UMQ 4UMR 4UMU
• Descriptor: MATERNAL EMBRYONIC LEUCINE ZIPPER KINASE, DIMETHYL SULFOXIDE, 1-(4-{[3-(isoquinolin-7-yl)prop-2-yn-1-yl]oxy}-2-methoxybenzyl)piperazinediium, ... (4 entities in total)
• Functional Keywords: transferase, fragment based drug design
• Biological source: HOMO SAPIENS (HUMAN)
• Cellular location: Cell membrane ; Peripheral membrane protein : Q14680
• Total number of polymer chains: 1
• Total formula weight: 41389.92

Authors

Johnson, C.N.,Berdini, V.,Beke, L.,Bonnet, P.,Brehmer, D.,Coyle, J.E.,Day, P.J.,Frederickson, M.,Freyne, E.J.E.,Gilissen, R.A.H.J.,Hamlett, C.C.F.,Howard, S.,Meerpoel, L.,McMenamin, R.,Patel, S.,Rees, D.C.,Sharff, A.,Sommen, F.,Wu, T.,Linders, J.T.M. (deposition date: 2014-05-21, release date: 2014-10-22, Last modification date: 2024-05-08)

Primary citation

Johnson, C.N.,Adelinet, C.,Berdini, V.,Beke, L.,Bonnet, P.,Brehmer, D.,Calo, F.,Coyle, J.E.,Day, P.J.,Frederickson, M.,Freyne, E.J.E.,Gilissen, R.A.H.J.,Hamlett, C.C.F.,Howard, S.,Meerpoel, L.,Mevellec, L.,Mcmenamin, R.,Pasquier, E.,Patel, S.,Rees, D.C.,Linders, J.T.M.
Structure-Based Design of Type II Inhibitors Applied to Maternal Embryonic Leucine Zipper Kinase.
Acs Med.Chem.Lett., 6:31-, 2015

PubMed Abstract: A novel Type II kinase inhibitor chemotype has been identified for maternal embryonic leucine zipper kinase (MELK) using structure-based ligand design. The strategy involved structural characterization of an induced DFG-out pocket by protein-ligand X-ray crystallography and incorporation of a slender linkage capable of bypassing a large gate-keeper residue, thus enabling design of molecules accessing both hinge and induced pocket regions. Optimization of an initial hit led to the identification of a low-nanomolar, cell-penetrant Type II inhibitor suitable for use as a chemical probe for MELK.

PubMed: 25589926
DOI: 10.1021/ML5001273

Experimental method

X-RAY DIFFRACTION (1.98 Å)