7X8M

NMR Solution Structure of the 2:1 Berberine-KRAS-G4 Complex

Summary for 7X8M

• Entry DOI: 10.2210/pdb7x8m/pdb
• Descriptor: DNA (24-MER), BERBERINE (2 entities in total)
• Functional Keywords: g-quadruplex, kras, berberine, dna
• Biological source: Homo sapiens
• Total number of polymer chains: 1
• Total formula weight: 8212.66

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

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: 36224201
DOI: 10.1038/s41467-022-33761-4

Experimental method

SOLUTION NMR