6PW3

LARP1 DM15 FYRE (F844Y, R847E) mutant bound to m7GpppG dinucleotide (capG)

Summary for 6PW3

• Entry DOI: 10.2210/pdb6pw3/pdb
• Descriptor: La-related protein 1, 7-METHYL-GUANOSINE-5'-TRIPHOSPHATE-5'-GUANOSINE, MAGNESIUM ION, ... (4 entities in total)
• Functional Keywords: heat-like, cap-binding, top mrna, translation regulation, rna binding protein
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 4
• Total formula weight: 80047.99

Authors

Lahr, R.M.,Berman, A.J. (deposition date: 2019-07-22, release date: 2019-11-06, Last modification date: 2023-10-11)

Primary citation

Cassidy, K.C.,Lahr, R.M.,Kaminsky, J.C.,Mack, S.,Fonseca, B.D.,Das, S.R.,Berman, A.J.,Durrant, J.D.
Capturing the Mechanism Underlying TOP mRNA Binding to LARP1.
Structure, 27:1771-, 2019

PubMed Abstract: The RNA-binding protein La-related protein 1 (LARP1) plays a central role in ribosome biosynthesis. Its C-terminal DM15 region binds the 7-methylguanosine (mG) cap and 5' terminal oligopyrimidine (TOP) motif characteristic of transcripts encoding ribosomal proteins and translation factors. Under the control of mammalian target of rapamycin complex 1 (mTORC1), LARP1 regulates translation of these transcripts. Characterizing the dynamics of DM15-TOP recognition is essential to understanding this fundamental biological process. We use molecular dynamics simulations, biophysical assays, and X-ray crystallography to reveal the mechanism of DM15 binding to TOP transcripts. Residues C-terminal to the mG-binding site play important roles in cap recognition. Furthermore, we show that the unusually static pocket that recognizes the +1 cytosine characteristic of TOP transcripts drives binding specificity. Finally, we demonstrate that the DM15 pockets involved in TOP-specific mGpppC-motif recognition are likely druggable. Collectively, these studies suggest unique opportunities for further pharmacological development.

PubMed: 31676287
DOI: 10.1016/j.str.2019.10.006

Experimental method

X-RAY DIFFRACTION (2.34 Å)