title: Gating by tryptophan 73 exposes a cryptic pocket at the protein-binding interface of the oncogenic eIF4E protein.
abstract: Targeting protein-protein interacting sites for potential therapeutic applications is a challenge in the development of inhibitors, and this becomes more difficult when these interfaces are relatively planar, as in the eukaryotic translation initiation factor 4E (eIF4E) protein. eIF4E is an oncogene that is overexpressed in numerous forms of cancer, making it a prime target as a therapeutic molecule. We report here the presence of a cryptic pocket at the protein-binding interface of eIF4E, which opens transiently during molecular dynamics simulations of the protein in solvent water and is observed to be stable when solvent water is mixed with benzene molecules. This pocket can also be seen in the ensemble of structures available from the solution-state conformations of eIF4E. The accessibility of the pocket is gated by the side-chain transitions of an evolutionarily conserved tryptophan residue. It is found to be feasible for accommodating clusters of benzene molecules, which signify the plasticity and ligandability of the pocket. We also observe that the newly formed cavity provides a favorable binding environment for interaction of a well-recognized small molecule inhibitor of eIF4E. The occurrence of this transiently accessible cavity highlights the existence of a more pronounced binding groove in a region that has traditionally been considered to be planar. Together, the data suggest that an alternate binding cavity exists on eIF4E and could be exploited for the rational design and development of a new class of lead compounds against the protein.
authors.affiliation: Bioinformatics Institute, A*STAR (Agency for Science, Technology and Research) , 30 Biopolis Street, #07-01 Matrix, Singapore 138671.
authors.forename: Dilraj
authors.initials: D
authors.lastname: Lama
authors.affiliation: p53 Laboratory, A*STAR (Agency for Science, Technology and Research) , 8A Biomedical Grove, #06-04/05, Neuros/Immunos, Singapore 138648.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Brown
authors.affiliation: p53 Laboratory, A*STAR (Agency for Science, Technology and Research) , 8A Biomedical Grove, #06-04/05, Neuros/Immunos, Singapore 138648.
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.|Department of Biological Sciences, National University of Singapore , 14 Science Drive 4, Singapore 117543.|School of Biological Sciences, Nanyang Technological University , 50 Nanyang Drive, Singapore 637551.
authors.forename: Chandra S
authors.initials: CS
authors.lastname: Verma
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000737:chemistry / Q000378:metabolism; D001554:Benzene; D018797:Cell Cycle Proteins; D017124:Conserved Sequence; D039561:Eukaryotic Initiation Factor-4E / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D039603:Eukaryotic Initiation Factor-4G / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D015513:Oncogene Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D010750:Phosphoproteins / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D011487:Protein Conformation; D054730:Protein Interaction Domains and Motifs / Q000235:genetics; D012997:Solvents; D014364:Tryptophan / Q000737:chemistry / Q000235:genetics; D014867:Water
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; C087000:EIF4EBP1 protein, human; C113920:EIF4G1 protein, human; D039561:Eukaryotic Initiation Factor-4E; D039603:Eukaryotic Initiation Factor-4G; D015513:Oncogene Proteins; D010750:Phosphoproteins; D012997:Solvents; D014867:Water; D014364:Tryptophan; D001554:Benzene