Water-Bridge Mediates Recognition of mRNA Cap in eIF4E

• Main Authors: Lama, Dilraj, Pradhan, Mohan R., Brown, Christopher J., Eapen, Rohan S., Joseph, Thomas L., Kwoh, Chee-Keong, Lane, David P., Verma, Chandra Shekhar
• Other Authors: School of Computer Science and Engineering
• Format: Article
• Language: English
• Published: 2017
• Subjects: Translation initiation factor 4E protein; 5′ mRNA cap
• Online Access: https://hdl.handle.net/10356/84992; http://hdl.handle.net/10220/42071
• Institution: Nanyang Technological University

Ligand binding pockets in proteins contain water molecules, which play important roles in modulating protein-ligand interactions. Available crystallographic data for the 5′ mRNA cap-binding pocket of the translation initiation factor protein eIF4E shows several structurally conserved waters, which also persist in molecular dynamics simulations. These waters engage an intricate hydrogen-bond network between the cap and protein. Two crystallographic waters in the cleft of the pocket show a high degree of conservation and bridge two residues, which are part of an evolutionarily conserved scaffold. This appears to be a preformed recognition module for the cap with the two structural waters facilitating an efficient interaction. This is also recapitulated in a new crystal structure of the apo protein. These findings open new windows for the design and screening of compounds targeting eIF4E.