5VT1

Crystal Structure of the Human CAMKK2B bound to a thiadiazinone benzamide inhibitor

Summary for 5VT1

• Entry DOI: 10.2210/pdb5vt1/pdb
• Descriptor: Calcium/calmodulin-dependent protein kinase kinase 2, 4-({5-[(3-hydroxy-4-methylphenyl)amino]-4-oxo-4H-1,2,6-thiadiazin-3-yl}amino)benzamide, MAGNESIUM ION, ... (4 entities in total)
• Functional Keywords: transferase, protein kinase domain, structural genomics, structural genomics consortium, sgc, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 33520.95

Authors

Counago, R.M.,Asquith, C.R.M.,Arruda, P.,Edwards, A.M.,Gileadi, O.,Kalogirou, A.S.,Koutentis, P.A.,Structural Genomics Consortium (SGC) (deposition date: 2017-05-15, release date: 2017-05-24, Last modification date: 2023-10-04)

Primary citation

Asquith, C.R.M.,Godoi, P.H.,Counago, R.M.,Laitinen, T.,Scott, J.W.,Langendorf, C.G.,Oakhill, J.S.,Drewry, D.H.,Zuercher, W.J.,Koutentis, P.A.,Willson, T.M.,Kalogirou, A.S.
1,2,6-Thiadiazinones as Novel Narrow Spectrum Calcium/Calmodulin-Dependent Protein Kinase Kinase 2 (CaMKK2) Inhibitors.
Molecules, 23:-, 2018

PubMed Abstract: We demonstrate for the first time that 4-1,2,6-thiadiazin-4-one (TDZ) can function as a chemotype for the design of ATP-competitive kinase inhibitors. Using insights from a co-crystal structure of a 3,5-bis(arylamino)-4-1,2,6-thiadiazin-4-one bound to calcium/calmodulin-dependent protein kinase kinase 2 (CaMKK2), several analogues were identified with micromolar activity through targeted displacement of bound water molecules in the active site. Since the TDZ analogues showed reduced promiscuity compared to their 2,4-dianilinopyrimidine counter parts, they represent starting points for development of highly selective kinase inhibitors.

PubMed: 29783765
DOI: 10.3390/molecules23051221

Experimental method

X-RAY DIFFRACTION (1.9 Å)