4YU2
Crystal structure of DYRK1A with harmine-derivatized AnnH-75 inhibitor
Summary for 4YU2
| Entry DOI | 10.2210/pdb4yu2/pdb |
| Descriptor | Dual specificity tyrosine-phosphorylation-regulated kinase 1A, TETRAETHYLENE GLYCOL, (1-chloro-7-methoxy-9H-beta-carbolin-9-yl)acetonitrile, ... (5 entities in total) |
| Functional Keywords | transferase, dyrk1a, down syndrome, inhibitor, harmine, structural genomics, structural genomics consortium, sgc |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 4 |
| Total formula weight | 170379.88 |
| Authors | Chaikuad, A.,Wurzlbauer, A.,Nowak, R.,von Delft, F.,Arrowsmith, C.H.,Edwards, A.M.,Bountra, C.,Bracher, F.,Knapp, S.,Structural Genomics Consortium (SGC) (deposition date: 2015-03-18, release date: 2015-03-25, Last modification date: 2024-11-20) |
| Primary citation | Wurzlbauer, A.,Ruben, K.,Gurdal, E.,Chaikuad, A.,Knapp, S.,Sippl, W.,Becker, W.,Bracher, F. How to Separate Kinase Inhibition from Undesired Monoamine Oxidase A Inhibition-The Development of the DYRK1A Inhibitor AnnH75 from the Alkaloid Harmine. Molecules, 25:-, 2020 Cited by PubMed Abstract: The β-carboline alkaloid harmine is a potent DYRK1A inhibitor, but suffers from undesired potent inhibition of MAO-A, which strongly limits its application. We synthesized more than 60 analogues of harmine, either by direct modification of the alkaloid or by de novo synthesis of β-carboline and related scaffolds aimed at learning about structure-activity relationships for inhibition of both DYRK1A and MAO-A, with the ultimate goal of separating desired DYRK1A inhibition from undesired MAO-A inhibition. Based on evidence from published crystal structures of harmine bound to each of these enzymes, we performed systematic structure modifications of harmine yielding DYRK1A-selective inhibitors characterized by small polar substituents at N-9 (which preserve DYRK1A inhibition and eliminate MAO-A inhibition) and beneficial residues at C-1 (methyl or chlorine). The top compound remains a potent DYRK1A inhibitor, and it is devoid of MAO-A inhibition. Its binding mode to DYRK1A was elucidated by crystal structure analysis, and docking experiments provided additional insights for this attractive series of DYRK1A and MAO-A inhibitors. PubMed: 33339338DOI: 10.3390/molecules25245962 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.9 Å) |
Structure validation
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