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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Regulators of G-protein Signaling accelerate GPCR signaling kinetics and govern sensitivity solely by accelerating GTPase activity
Nevin A. Lambert,Christopher A. Johnston,Christopher A. Johnston,Steven D. Cappell,Sudhakiranmayi Kuravi,Adam J. Kimple,Francis S. Willard,Francis S. Willard,David P. Siderovski +8 more
TL;DR: Gα-directed GAP activity, the first biochemical function ascribed to RGS proteins, is sufficient to explain the activation kinetics and agonist sensitivity observed from G-protein–coupled receptor (GPCR) signaling in a cellular context.
Journal ArticleDOI
G Protein Signaling: Insights from New Structures
TL;DR: Determination of the crystal structures of these G proteins has led to a mechanistic understanding of their function, and structures of G proteins in complex with other signaling partners reveal details of how signaling through these highly evolutionarily conserved molecules is regulated within the cell.
Journal ArticleDOI
Conjugative plasmid protein TrwB, an integral membrane type IV secretion system coupling protein. Detailed structural features and mapping of the active site cleft.
TL;DR: The structure of a soluble TrwB variant unveils an elongated molecule with six equivalent protein units featuring a spherical quaternary structure, leaving a central channel for substrate binding and putative hydrolysis.
Journal ArticleDOI
Regulators of G-protein signalling: a novel protein family involved in timely deactivation and desensitization of signalling via heterotrimeric G proteins.
Thomas Wieland,Ching-Kang Chen +1 more
TL;DR: The proposed mechanism by which RGS proteins exert GAP activity for G-protein α-subunits as well as their specificities are discussed, and the role of R GS proteins in desensitization and temporal resolution in certain signalling pathways will also be addressed.
Journal ArticleDOI
Direct targeting of Gαq and Gα11 oncoproteins in cancer cells
Suvi Annala,Xiaodong Feng,Naveen Shridhar,Funda Eryilmaz,Julian Patt,Ju Hee Yang,Eva Marie Pfeil,Rodolfo Daniel Cervantes-Villagrana,Asuka Inoue,Felix Häberlein,Tanja Slodczyk,Raphael Reher,Stefan Kehraus,Stefania Monteleone,Ramona Schrage,Nina Heycke,Ulrike Rick,Sandra Engel,Alexander Pfeifer,Peter Kolb,Gabriele M. König,Moritz Bünemann,Thomas Tüting,José Vázquez-Prado,J. Silvio Gutkind,Evelyna Gaffal,Evi Kostenis +26 more
TL;DR: It is reported that the cyclic depsipeptide FR900359 directly interacted with GTPase-deficient Gαq/11 proteins and preferentially inhibited mitogenic ERK signaling rather than canonical phospholipase Cβ (PLCβ) signaling driven by these oncogenes.
References
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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.