4YZM

Humanized Roco4 bound to LRRK2-In1

Summary for 4YZM

• Entry DOI: 10.2210/pdb4yzm/pdb
• Descriptor: Probable serine/threonine-protein kinase roco4, 2-[(2-methoxy-4-{[4-(4-methylpiperazin-1-yl)piperidin-1-yl]carbonyl}phenyl)amino]-5,11-dimethyl-5,11-dihydro-6H-pyrimido[4,5-b][1,4]benzodiazepin-6-one, MAGNESIUM ION, ... (4 entities in total)
• Functional Keywords: roco-protein, kinase, lrrk2, inhibitor, transferase
• Biological source: Dictyostelium discoideum (Slime mold)
• Total number of polymer chains: 2
• Total formula weight: 66287.00

Authors

Gilsbach, B.K.,Messias, A.C.,Ito, G.,Sattler, M.,Alessi, D.R.,Wittinghofer, A.,Kortholt, A. (deposition date: 2015-03-25, release date: 2015-05-06, Last modification date: 2024-01-10)

Primary citation

Gilsbach, B.K.,Messias, A.C.,Ito, G.,Sattler, M.,Alessi, D.R.,Wittinghofer, A.,Kortholt, A.
Structural Characterization of LRRK2 Inhibitors.
J.Med.Chem., 58:3751-3756, 2015

PubMed Abstract: Kinase inhibition is considered to be an important therapeutic target for LRRK2 mediated Parkinson's disease (PD). Many LRRK2 kinase inhibitors have been reported but have yet to be optimized in order to qualify as drug candidates for the treatment of the disease. In order to start a structure-function analysis of such inhibitors, we mutated the active site of Dictyostelium Roco4 kinase to resemble LRRK2. Here, we show saturation transfer difference (STD) NMR and the first cocrystal structures of two potent in vitro inhibitors, LRRK2-IN-1 and compound 19, with mutated Roco4. Our data demonstrate that this system can serve as an excellent tool for the structural characterization and optimization of LRRK2 inhibitors using X-ray crystallography and NMR spectroscopy.

PubMed: 25897865
DOI: 10.1021/jm5018779

Experimental method

X-RAY DIFFRACTION (3 Å)