Journal ArticleDOI
Structures of active conformations of Gi alpha 1 and the mechanism of GTP hydrolysis.
David E. Coleman,Albert M. Berghuis,Ethan Lee,Maurine E. Linder,Alfred G. Gilman,Stephen R. Sprang +5 more
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TLDR
AlF4- complexes formed by the G protein Gi alpha 1 demonstrate specific roles in transition-state stabilization for two highly conserved residues, suggesting a mechanism that may promote release of the beta gamma subunit complex when the alpha subunit is activated by GTP.Abstract:
Mechanisms of guanosine triphosphate (GTP) hydrolysis by members of the G protein alpha subunit-p21ras superfamily of guanosine triphosphatases have been studied extensively but have not been well understood. High-resolution x-ray structures of the GTP gamma S and GDP.AlF4- complexes formed by the G protein Gi alpha 1 demonstrate specific roles in transition-state stabilization for two highly conserved residues. Glutamine204 (Gln61 in p21ras) stabilizes and orients the hydrolytic water in the trigonal-bipyramidal transition state. Arginine 178 stabilizes the negative charge at the equatorial oxygen atoms of the pentacoordinate phosphate intermediate. Conserved only in the G alpha family, this residue may account for the higher hydrolytic rate of G alpha proteins relative to those of the p21ras family members. The fold of Gi alpha 1 differs from that of the homologous Gt alpha subunit in the conformation of a helix-loop sequence located in the alpha-helical domain that is characteristic of these proteins; this site may participate in effector binding. The amino-terminal 33 residues are disordered in GTP gamma S-Gi alpha 1, suggesting a mechanism that may promote release of the beta gamma subunit complex when the alpha subunit is activated by GTP.read more
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Cytochrome P450 11A1 Bioactivation of a Kinase Inhibitor in Rats: Use of Radioprofiling, Modulation of Metabolism, and Adrenocortical Cell Lines to Evaluate Adrenal Toxicity
Donglu Zhang,Oliver P. Flint,Lifei Wang,Ashok Kumar Gupta,Richard A. Westhouse,Weiping Zhao,Nirmala Raghavan,Janet Caceres-Cortes,Punit Marathe,Guoxiang Shen,Yueping Zhang,Alban Allentoff,Jonathan L. Josephs,Jinping Gan,Robert M. Borzilleri,W. Griffith Humphreys +15 more
TL;DR: Results are consistent with a CYP11A1-mediated bioactivation to generate a reactive species, covalent binding to proteins, and subsequently rat adrenal toxicity, and cross-species adrenaloxicity potential of this compound and related analogues.
Journal ArticleDOI
Effect of N-Terminal Myristoylation on the Active Conformation of Gαi1–GTP
TL;DR: The results suggest that lipidation is also important for protein-protein interactions during signal transduction and emphasize the importance of permanent lipid attachment for the conformation and functional tunability of signaling proteins.
Journal ArticleDOI
A novel Raman spectrophotometric method for quantitative measurement of nucleoside triphosphate hydrolysis
TL;DR: The reliability of the Raman method is demonstrated for the NTPase-active RNA-packaging enzyme (protein P4) of bacteriophage phi6, and its applicability to a variety of nucleotide substrates of P4 is demonstrated, including the natural ribonucleoside triphosphates (ATP, GTP) and dideoxynucleosid triph phosphates (dd ATP, ddGTP).
Journal ArticleDOI
Receptor-mediated changes at the myristoylated amino terminus of Gαil proteins
TL;DR: This work demonstrates that the myristoylated amino terminus of Galpha il proteins undergoes receptor-mediated changes during the dynamic process of G protein signaling.
Journal ArticleDOI
Exploring allosteric coupling in the α-subunit of Heterotrimeric G proteins using evolutionary and ensemble-based approaches
TL;DR: This information can be used as a guide to structural, spectroscopic, mutational, and theoretical studies on the allosteric network in Gα proteins, which will provide a better understanding of G protein-mediated signal transduction.
References
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Journal ArticleDOI
PROCHECK: a program to check the stereochemical quality of protein structures
TL;DR: The PROCHECK suite of programs as mentioned in this paper provides a detailed check on the stereochemistry of a protein structure and provides an assessment of the overall quality of the structure as compared with well refined structures of the same resolution.
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MOLSCRIPT: a program to produce both detailed and schematic plots of protein structures
TL;DR: The MOLSCRIPT program as discussed by the authors produces plots of protein structures using several different kinds of representations, including simple wire models, ball-and-stick models, CPK models and text labels.
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G proteins: transducers of receptor-generated signals
TL;DR: This paper presents a meta-analysis of G Protein Interactions and its Foundations, which states that G Proteins are Law-Regulated and G Protein-Effector Interactions are Nonvolatile.
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Free R value: a novel statistical quantity for assessing the accuracy of crystal structures.
TL;DR: In this article, a statistical quantity (RfreeT) is defined to measure the agreement between observed and computed structure factor amplitudes for a 'test' set of reflections that is omitted in the modelling and refinement process.
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The GTPase superfamily: conserved structure and molecular mechanism
TL;DR: GTPases are conserved molecular switches, built according to a common structural design, and rapidly accruing knowledge of individual GTPases—crystal structures, biochemical properties, or results of molecular genetic experiments—support and generate hypotheses relating structure to function in other members of the diverse family of GTPase.