7SXP

G-quadruplex structure formed in the NRAS mRNA with a G8U substitution

Summary for 7SXP

• Entry DOI: 10.2210/pdb7sxp/pdb
• Descriptor: NRAS mRNA, POTASSIUM ION, CACODYLIC ACID (3 entities in total)
• Functional Keywords: g-quadruplex, nras, rna
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 7635.61

Authors

Banco, M.T.,Ferre-D'Amare, A.R. (deposition date: 2021-11-24, release date: 2023-05-31, Last modification date: 2024-05-22)

Primary citation

Balaratnam, S.,Torrey, Z.R.,Calabrese, D.R.,Banco, M.T.,Yazdani, K.,Liang, X.,Fullenkamp, C.R.,Seshadri, S.,Holewinski, R.J.,Andresson, T.,Ferre-D'Amare, A.R.,Incarnato, D.,Schneekloth Jr., J.S.
Investigating the NRAS 5' UTR as a target for small molecules.
Cell Chem Biol, 30:643-657.e8, 2023

PubMed Abstract: Neuroblastoma RAS (NRAS) is an oncogene that is deregulated and highly mutated in cancers including melanomas and acute myeloid leukemias. The 5' untranslated region (UTR) (5' UTR) of the NRAS mRNA contains a G-quadruplex (G4) that regulates translation. Here we report a novel class of small molecule that binds to the G4 structure located in the 5' UTR of the NRAS mRNA. We used a small molecule microarray screen to identify molecules that selectively bind to the NRAS-G4 with submicromolar affinity. One compound inhibits the translation of NRAS in vitro but showed only moderate effects on the NRAS levels in cellulo. Rapid Amplification of cDNA Ends and RT-PCR analysis revealed that the predominant NRAS transcript does not possess the G4 structure. Thus, although NRAS transcripts lack a G4 in many cell lines the concept of targeting folded regions within 5' UTRs to control translation remains a highly attractive strategy.

PubMed: 37257453
DOI: 10.1016/j.chembiol.2023.05.004

Experimental method

X-RAY DIFFRACTION (2.9 Å)