6U5L
Structure of human ULK4 in complex with an inhibitor
Summary for 6U5L
| Entry DOI | 10.2210/pdb6u5l/pdb |
| Descriptor | Serine/threonine-protein kinase ULK4, N~2~-(1H-benzimidazol-6-yl)-N~4~-(5-cyclobutyl-1H-pyrazol-3-yl)quinazoline-2,4-diamine, GLYCEROL, ... (5 entities in total) |
| Functional Keywords | kinase, pseudokinase, transferase, transferase-transferase inhibitor complex, transferase/transferase inhibitor |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 1 |
| Total formula weight | 33191.07 |
| Authors | Khamrui, S.,Lazarus, M.B. (deposition date: 2019-08-28, release date: 2019-12-25, Last modification date: 2023-10-11) |
| Primary citation | Khamrui, S.,Ung, P.M.U.,Secor, C.,Schlessinger, A.,Lazarus, M.B. High-Resolution Structure and Inhibition of the Schizophrenia-Linked Pseudokinase ULK4. J.Am.Chem.Soc., 142:33-37, 2020 Cited by PubMed Abstract: The ULK (UNC51-like) enzymes are a family of mammalian kinases that have critical roles in autophagy and development. While ULK1, ULK2, and ULK3 have been characterized, very little is known about ULK4. However, recently, deletions in ULK4 have been genetically linked to increased susceptibility to developing schizophrenia, a devastating neuropsychiatric disease with high heritability but few genes identified. Interestingly, ULK4 is a pseudokinase with some unusual mutations in the kinase catalytic motifs. Here, we report the first structure of the human ULK4 kinase at high resolution and show that although ULK4 has no apparent phosphotransfer activity, it can strongly bind ATP. We find an unusual mechanism for binding ATP in a Mg-independent manner, including a rare hydrophobic bridge in the active site. In addition, we develop two assays for ATP binding to ULK4, perform a virtual and experimental screen to identify small-molecule binders of ULK4, and identify several novel scaffolds that bind ULK4 and can lead the way to more selective small molecules that may help shed light on the function of this enigmatic protein. PubMed: 31841327DOI: 10.1021/jacs.9b10458 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.75 Å) |
Structure validation
Download full validation report
