title: Water-Bridge Mediates Recognition of mRNA Cap in eIF4E.
abstract: 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.
authors.affiliation: Bioinformatics Institute, A(∗)STAR (Agency for Science, Technology and Research), 30 Biopolis Street, #07-01 Matrix, Singapore 138671, Singapore. Electronic address: dilrajl@bii.a-star.edu.sg.
authors.forename: Dilraj
authors.initials: D
authors.lastname: Lama
authors.affiliation: Bioinformatics Institute, A(∗)STAR (Agency for Science, Technology and Research), 30 Biopolis Street, #07-01 Matrix, Singapore 138671, Singapore; School of Computer Engineering, Nanyang Technological University, 50 Nanyang Avenue, Singapore 639798, Singapore.
authors.forename: Mohan R
authors.initials: MR
authors.lastname: Pradhan
authors.affiliation: p53 Laboratory, A(∗)STAR (Agency for Science, Technology and Research), 8A Biomedical Grove, #06-04/05, Neuros/Immunos, Singapore 138648, Singapore.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Brown
authors.affiliation: School of Molecular and Cellular Biology, University of Leeds, Leeds LS2 9JT, UK.
authors.forename: Rohan S
authors.initials: RS
authors.lastname: Eapen
authors.affiliation: Bioinformatics Institute, A(∗)STAR (Agency for Science, Technology and Research), 30 Biopolis Street, #07-01 Matrix, Singapore 138671, Singapore.
authors.forename: Thomas L
authors.initials: TL
authors.lastname: Joseph
authors.affiliation: School of Computer Engineering, Nanyang Technological University, 50 Nanyang Avenue, Singapore 639798, Singapore.
authors.forename: Chee-Keong
authors.initials: CK
authors.lastname: Kwoh
authors.affiliation: p53 Laboratory, A(∗)STAR (Agency for Science, Technology and Research), 8A Biomedical Grove, #06-04/05, Neuros/Immunos, Singapore 138648, Singapore.
authors.forename: David P
authors.initials: DP
authors.lastname: Lane
authors.affiliation: Bioinformatics Institute, A(∗)STAR (Agency for Science, Technology and Research), 30 Biopolis Street, #07-01 Matrix, Singapore 138671, Singapore; Department of Biological Sciences, National University of Singapore, 14 Science Drive 4, Singapore 117543, Singapore; School of Biological Sciences, Nanyang Technological University, 50 Nanyang Drive, Singapore 637551, Singapore. Electronic address: chandra@bii.a-star.edu.sg.
authors.forename: Chandra S
authors.initials: CS
authors.lastname: Verma
mesh_terms: D001665:Binding Sites; D017124:Conserved Sequence; D018360:Crystallography, X-Ray; D039561:Eukaryotic Initiation Factor-4E / Q000737:chemistry* / Q000378:metabolism*; D006860:Hydrogen Bonding; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D012315:RNA Caps / Q000378:metabolism*; D014867:Water / Q000378:metabolism*
chemical_list: D039561:Eukaryotic Initiation Factor-4E; D012315:RNA Caps; D014867:Water
keywords: 5′ mRNA cap; X-ray crystallography; comparative structure analysis; conserved structural waters; evolutionarily conserved residues; molecular dynamics simulations; mutations; translation initiation factor 4E protein; water-bridge recognition module