8Q69
Crystal structure of HsRNMT complexed with inhibitor DDD1060606
Summary for 8Q69
| Entry DOI | 10.2210/pdb8q69/pdb |
| Related | 5E8J |
| Descriptor | mRNA cap guanine-N7 methyltransferase, S-ADENOSYL-L-HOMOCYSTEINE, 1-[(3~{S})-3-(2~{H}-pyrazolo[3,4-b]pyridin-3-yl)piperidin-1-yl]-2-thiophen-3-yl-ethanone, ... (6 entities in total) |
| Functional Keywords | methyl transferase, rna binding protein |
| Biological source | Homo sapiens (human) More |
| Total number of polymer chains | 2 |
| Total formula weight | 66806.99 |
| Authors | Petit, A.P.,Fyfe, P.K. (deposition date: 2023-08-11, release date: 2024-08-21, Last modification date: 2025-03-12) |
| Primary citation | Pearson, L.A.,Petit, A.P.,Mendoza Martinez, C.,Bellany, F.,Lin, D.,Niven, S.,Swift, R.,Eadsforth, T.,Fyfe, P.,Paul, M.,Postis, V.,Hu, X.,Cowling, V.H.,Gray, D.W. Characterisation of RNA guanine-7 methyltransferase (RNMT) using a small molecule approach. Biochem.J., 482:-, 2025 Cited by PubMed Abstract: The maturation of the RNA cap involving guanosine N-7 methylation, catalyzsed by the HsRNMT (RNA guanine-7 methyltransferase (HsRNMT)-RAM (RNA guanine-N7 methyltransferase activating subunit (RAM) complex, is currently under investigation as a novel strategy to combat PIK3CA -mutant breast cancer. However, the development of effective drugs is hindered by a limited understanding of the enzyme's mechanism and a lack of small molecule inhibitors. Following the elucidation of the HsRNMT-RAM molecular mechanism, we report the biophysical characterizsation of two small molecule hits. Biophysics, biochemistry and structural biology confirm that both compounds bind competitively with cap and bind effectively to HsRNMT-RAM in the presence of the co-product SAH, with a binding affinity (KD) of approximately 1 μM. This stabilisation of the enzyme--product complex results in uncompetitive inhibition. Finally, we describe the properties of the cap pocket and provided suggestions for further development of the tool compounds. PubMed: 39869500DOI: 10.1042/BCJ20240608 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.96 Å) |
Structure validation
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