5dk4 | pdb_00005dk4

Crystal structure analysis of Tryptophanyl-trna synthetase from Bacillus stearothermophilus in complex with indolmycin and Mg*ATP

spinqualitylabelsall models 5dk4, resolution 1.90Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 5dk4 is a 1 chain structure with sequence from Geobacillus stearothermophilus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.9Å Ligands: 5BX, ATP, GOL, MG, MSE Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function SYW_GEOSE Publication Abstract from PubMed Indolmycin is a natural tryptophan analog that competes with tryptophan for binding to tryptophanyl-tRNA synthetase (TrpRS) enzymes. Bacterial and eukaryotic cytosolic TrpRSs have comparable affinities for tryptophan, Km ~2 muM, and yet only bacterial TrpRSs are inhibited by indolmycin. Despite the similarity between these ligands, Bacillus stearothermophilus (Bs)TrpRS preferentially binds indolmycin ~1500-fold tighter than its tryptophan substrate. Kinetic characterization and crystallographic analysis of BsTrpRS allowed us to probe novel aspects of indolmycin inhibitory action. Previous work had revealed that long-range coupling to residues within an allosteric region called the D1 switch of BsTrpRS positions the Mg2+ ion in a manner that allows it to assist in transition-state stabilization. The Mg2+ ion in the inhibited complex forms significantly closer contacts with non-bridging oxygen atoms from each phosphate group of ATP and three water molecules than occur in the (presumably catalytically competent) pre-transition state (preTS) crystal structures. We propose that this altered coordination, stabilizes a ground-state Mg2+.ATP configuration, accounting for the high-affinity inhibition of BsTrpRS by indolmycin. Conversely, both the ATP configuration and Mg2+ coordination in the human cytosolic (Hc)TrpRS preTS structure differ greatly from the BsTrpRS preTS structure. The effect of these differences is that catalysis occurs via a different transition state stabilization mechanism in HcTrpRS, with a yet-to-be determined role for Mg2+. Modeling indolmycin into the tryptophan binding site points to steric hindrance and an inability to retain the interactions used for tryptophan substrate recognition as causes for the 1000-fold weaker indolmycin affinity to HcTrpRS. Selective Inhibition of Bacterial Tryptophanyl-tRNA Synthetases by Indolmycin is Mechanism-Based.,Williams TL, Yin WY, Carter CW Jr J Biol Chem. 2015 Nov 9. pii: jbc.M115.690321. PMID:26555258 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Aminoacyl tRNA synthetase 3D structures

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