3DTC
Crystal structure of mixed-lineage kinase MLK1 complexed with compound 16
Summary for 3DTC
| Entry DOI | 10.2210/pdb3dtc/pdb |
| Descriptor | Mitogen-activated protein kinase kinase kinase 9, SULFATE ION, 12-(2-hydroxyethyl)-2-(1-methylethoxy)-13,14-dihydronaphtho[2,1-a]pyrrolo[3,4-c]carbazol-5(12H)-one, ... (4 entities in total) |
| Functional Keywords | mixed-lineage kinase, mlk family, mlk1 and mlk3 subtype selective inhibitors, alternative splicing, atp-binding, kinase, nucleotide-binding, phosphoprotein, polymorphism, serine/threonine-protein kinase, sh3 domain, transferase |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 1 |
| Total formula weight | 30772.65 |
| Authors | Fedorov, A.A.,Fedorov, E.V.,Meyer, S.L.,Hudkins, R.L.,Almo, S.C. (deposition date: 2008-07-14, release date: 2009-03-31, Last modification date: 2024-02-21) |
| Primary citation | Hudkins, R.L.,Diebold, J.L.,Tao, M.,Josef, K.A.,Park, C.H.,Angeles, T.S.,Aimone, L.D.,Husten, J.,Ator, M.A.,Meyer, S.L.,Holskin, B.P.,Durkin, J.T.,Fedorov, A.A.,Fedorov, E.V.,Almo, S.C.,Mathiasen, J.R.,Bozyczko-Coyne, D.,Saporito, M.S.,Scott, R.W.,Mallamo, J.P. Mixed-lineage kinase 1 and mixed-lineage kinase 3 subtype-selective dihydronaphthyl[3,4-a]pyrrolo[3,4-c]carbazole-5-ones: optimization, mixed-lineage kinase 1 crystallography, and oral in vivo activity in 1-methyl-4-phenyltetrahydropyridine models. J.Med.Chem., 51:5680-5689, 2008 Cited by PubMed Abstract: The optimization of the dihydronaphthyl[3,4-a]pyrrolo[3,4-c]carbazole-5-one R(2) and R(12) positions led to the identification of the first MLK1 and MLK3 subtype-selective inhibitors within the MLK family. Compounds 14 (CEP-5104) and 16 (CEP-6331) displayed good potency for MLK1 and MLK3 inhibition with a greater than 30- to 100-fold selectivity for related family members MLK2 and DLK. Compounds 14 and 16 were orally active in vivo in a mouse MPTP biochemical efficacy model that was comparable to the first-generation pan-MLK inhibitor 1 (CEP-1347). The MLK1 structure-activity relationships were supported by the first-reported X-ray crystal structure of MLK1 bound with 16. PubMed: 18714982DOI: 10.1021/jm8005838 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.6 Å) |
Structure validation
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