5W5Q

MAP4K4 in complex with inhibitor compound 12 (N3-methyl-10-(3-methyl-3-(5-methyloxazol-2-yl)but-1-yn-1-yl)-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2,3-dicarboxamide)

Summary for 5W5Q

• Entry DOI: 10.2210/pdb5w5q/pdb
• Descriptor: Mitogen-activated protein kinase kinase kinase kinase 4, (5s,7s)-N~3~-methyl-10-[3-methyl-3-(5-methyl-1,3-oxazol-2-yl)but-1-yn-1-yl]-6,7-dihydro-5H-5,7-methanoimidazo[2,1-a][2]benzazepine-2,3-dicarboxamide (3 entities in total)
• Functional Keywords: kinase, transferase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 76183.65

Authors

Harris, S.F.,Wu, P. (deposition date: 2017-06-15, release date: 2018-06-20, Last modification date: 2024-03-13)

Primary citation

Feng, J.A.,Lee, P.,Alaoui, M.H.,Barrett, K.,Castanedo, G.,Godemann, R.,McEwan, P.,Wang, X.,Wu, P.,Zhang, Y.,Harris, S.F.,Staben, S.T.
Structure Based Design of Potent Selective Inhibitors of Protein Kinase D1 (PKD1).
Acs Med.Chem.Lett., 10:1260-1265, 2019

PubMed Abstract: We previously disclosed a series of type I 1/2 inhibitors of NF-κB inducing kinase (NIK). Inhibition of NIK by these compounds was found to be strongly dependent on the inclusion and absolute stereochemistry of a propargyl tertiary alcohol as it forms critical hydrogen bonds (H-bonds) with NIK. We report that inhibition of protein kinase D1 (PKD1) by this class of compounds is not dependent on H-bond interactions of this tertiary alcohol. This feature was leveraged in the design of highly selective inhibitors of PKD1 that no longer inhibit NIK. A structure-based hypothesis based on the position and flexibility of the α-C-helix of PKD1 vs NIK is presented.

PubMed: 31531194
DOI: 10.1021/acsmedchemlett.8b00658

Experimental method

X-RAY DIFFRACTION (2.33 Å)