2w97 | pdb_00002w97
CRYSTAL STRUCTURE OF EIF4E BOUND TO GLYCEROL AND EIF4G1 PEPTIDE
Structural highlights
Disease[IF4G1_HUMAN] Defects in EIF4G1 are the cause of Parkinson disease type 18 (PARK18) [MIM:614251]. An autosomal dominant, late-onset form of Parkinson disease. Parkinson disease is a complex neurodegenerative disorder characterized by bradykinesia, resting tremor, muscular rigidity and postural instability, as well as by a clinically significant response to treatment with levodopa. The pathology involves the loss of dopaminergic neurons in the substantia nigra and the presence of Lewy bodies (intraneuronal accumulations of aggregated proteins), in surviving neurons in various areas of the brain.[1] Function[IF4E_HUMAN] Its translation stimulation activity is repressed by binding to the complex CYFIP1-FMR1 (By similarity). Recognizes and binds the 7-methylguanosine-containing mRNA cap during an early step in the initiation of protein synthesis and facilitates ribosome binding by inducing the unwinding of the mRNAs secondary structures. Component of the CYFIP1-EIF4E-FMR1 complex which binds to the mRNA cap and mediates translational repression. In the CYFIP1-EIF4E-FMR1 complex this subunit mediates the binding to the mRNA cap.[2] [IF4G1_HUMAN] Component of the protein complex eIF4F, which is involved in the recognition of the mRNA cap, ATP-dependent unwinding of 5'-terminal secondary structure and recruitment of mRNA to the ribosome. Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMedAn X-ray crystal structure of the eIF4E peptide complex is described in which two such complexes are located in the asymmetric unit. One of these complexes has m(7)GTP bound in a conformation which has been observed in several eIF4E crystal structures, whilst the other complex is free of m(7)GTP and contains a unique glycerol. The two complexes show significant structural differences between each other in the cap-binding site. The glycerol bound structure shows a reorientation of the W102 side chain out of the cap-binding site, disordering of the W56 containing loop and rotation of the carboxyl side-chain of E103. This is accompanied by movement of the M101 side chain into a position where W56 in the m(7)GTP bound complex would otherwise occupy. Rotation of the W102 sidechain also displaces a structured water molecule to a new site. This novel conformation of eIF4E with glycerol bound is hypothesized to be an intermediate state between the apo and m(7)GTP bound forms of eIF4E. These insights should prove useful in the design of inhibitors of eIF4E for cancer therapy. Crystallization of eIF4E complexed with eIF4GI peptide and glycerol reveals distinct structural differences around the cap-binding site.,Brown CJ, Verma CS, Walkinshaw MD, Lane DP Cell Cycle. 2009 Jun 15;8(12):1905-11. Epub 2009 Jun 15. PMID:19440045[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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