7X8O
NMR Solution Structure of the 2:1 Coptisine-KRAS-G4 Complex
Summary for 7X8O
| Entry DOI | 10.2210/pdb7x8o/pdb |
| Descriptor | DNA (24-MER), 6,7-dihydro[1,3]dioxolo[4,5-g][1,3]dioxolo[7,8]isoquino[3,2-a]isoquinolin-5-ium (2 entities in total) |
| Functional Keywords | g-quadruplex, kras, coptisine, dna |
| Biological source | Homo sapiens |
| Total number of polymer chains | 1 |
| Total formula weight | 8180.57 |
| Authors | Wang, K.B.,Liu, Y.,Li, J.,Xiao, C.,Gu, W.,Li, Y.,Xia, Y.Z.,Yan, T.,Yang, M.H.,Kong, L.Y. (deposition date: 2022-03-14, release date: 2022-09-07, Last modification date: 2024-05-15) |
| Primary citation | Wang, K.B.,Liu, Y.,Li, J.,Xiao, C.,Wang, Y.,Gu, W.,Li, Y.,Xia, Y.Z.,Yan, T.,Yang, M.H.,Kong, L.Y. Structural insight into the bulge-containing KRAS oncogene promoter G-quadruplex bound to berberine and coptisine. Nat Commun, 13:6016-6016, 2022 Cited by PubMed Abstract: KRAS is one of the most highly mutated oncoproteins, which is overexpressed in various human cancers and implicated in poor survival. The G-quadruplex formed in KRAS oncogene promoter (KRAS-G4) is a transcriptional modulator and amenable to small molecule targeting. However, no available KRAS-G4-ligand complex structure has yet been determined, which seriously hinders the structure-based rational design of KRAS-G4 targeting drugs. In this study, we report the NMR solution structures of a bulge-containing KRAS-G4 bound to berberine and coptisine, respectively. The determined complex structure shows a 2:1 binding stoichiometry with each compound recruiting the adjacent flacking adenine residue to form a "quasi-triad plane" that stacks over the two external G-tetrads. The binding involves both π-stacking and electrostatic interactions. Moreover, berberine and coptisine significantly lowered the KRAS mRNA levels in cancer cells. Our study thus provides molecular details of ligand interactions with KRAS-G4 and is beneficial for the design of specific KRAS-G4-interactive drugs. PubMed: 36224201DOI: 10.1038/s41467-022-33761-4 PDB entries with the same primary citation |
| Experimental method | SOLUTION NMR |
Structure validation
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