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David G. Lambright

Bio: David G. Lambright is an academic researcher from University of Massachusetts Medical School. The author has contributed to research in topics: GTPase & Rab. The author has an hindex of 48, co-authored 90 publications receiving 9265 citations. Previous affiliations of David G. Lambright include University of Massachusetts Amherst & Stanford University.


Papers
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Journal ArticleDOI
25 Jan 1996-Nature
TL;DR: The structure of a heterotrimeric G protein reveals the mechanism of the nucleotide-dependent engagement of the α and βγ subunits that regulates their interaction with receptor and effector molecules.
Abstract: The structure of a heterotrimeric G protein reveals the mechanism of the nucleotide-dependent engagement of the alpha and beta gamma subunits that regulates their interaction with receptor and effector molecules. The interaction involves two distinct interfaces and dramatically alters the conformation of the alpha but not of the beta gamma subunits. The location of the known sites for post-translational modification and receptor coupling suggest a plausible orientation with respect to the membrane surface and an activated heptahelical receptor.

1,138 citations

Journal ArticleDOI
25 Jan 1996-Nature
TL;DR: The crystal structure of the βγ dimer of the G protein transducin is solved using multiwavelength anomalous diffraction data to solve the interactions between G protein β- and γ-subunits and highlights regions implicated in effector modulation for the conserved family of G proteinβγ dimers.
Abstract: Many signalling cascades use seven-helical transmembrane receptors coupled to heterotrimeric G proteins (G alpha beta gamma) to convert extracellular signals into intracellular responses. Upon nucleotide exchange catalysed by activated receptors, heterotrimers dissociate into GTP-bound G alpha subunits and G beta gamma dimers, either of which can modulate many downstream effectors. Here we use multiwavelength anomalous diffraction data to solve the crystal structure of the beta gamma dimer of the G protein transducin. The beta-subunit is primarily a seven-bladed beta-propeller that is partially encircled by an extended gamma-subunit. The beta-propeller, which contains seven structurally similar WD repeats, defines the stereochemistry of the WD repeat and the probable architecture of all WD-repeat-containing domains. The structure details interactions between G protein beta- and gamma-subunits and highlights regions implicated in effector modulation for the conserved family of G protein beta gamma dimers.

714 citations

Journal ArticleDOI
23 Jun 1994-Nature
TL;DR: The 1.8 Å crystal structure of transducin α-GDP, when compared to that of the activated complex with GTP-γS, reveals the nature of the conformational changes that occur on activation of a heterotrimeric G-protein α-subunit.
Abstract: The 1.8 A crystal structure of transducin α-GDP, when compared to that of the activated complex with GTP-γS, reveals the nature of the conformational changes that occur on activation of a heterotrimeric G-protein α-subunit. Structural changes initiated by direct contacts with the terminal phosphate of GTP propagate to regions that have been implicated in effector activation. The changes are distinct from those observed in other members of the GTPase superfamily.

620 citations

Journal ArticleDOI
17 Nov 1994-Nature
TL;DR: In this article, the crystal structure of transducin a o GDP acti-vated with aluminium fluoride (Gtα·GDP·A1F−4·H2O) at 1.7 A was derived from three independent representations in the asymmetric unit.
Abstract: ALUMINIUM fluoride (A1F−4) activates members of the hetero-trimeric G-protein (Gαβγ) family1,2 by binding to inactive Gα·GDP near the site occupied by the γ-phosphate in Gα·GTP (ref. 3). Here we describe the crystal structure of transducin a o GDP acti-vated with aluminium fluoride (Gtα·GDP·A1F−4·H·O) at 1.7 A, a resolution sufficient to establish the coordination geometry of the bound aluminium fluoride as well as the extensive network of direct and water-mediated interactions that stabilize it. These observations are derived from three independent representations in the asymmetric unit, eliminating any chance of drawing conclu-sions based on stereochemistry imposed by crystal packing. Surprisingly, aluminium fluoride activates Gα·GDP by binding with a geometry resembling a pentavalent intermediate for GTP hydrolysis. The stabilizing interactions involve not only residues that interact with the y-phosphate in Gtα·GTPγS, but also conserved residues essential for GTPase activity. Thus the Gtα·GDP·AIF−4·H2O structure provides new insight into the mechanism of GTP hydrolysis.

544 citations

Journal ArticleDOI
TL;DR: Structural and cell biological studies shed new light on the mechanisms of Rab GEF and GAP action, and the cellular trafficking pathways they act in.

407 citations


Cited by
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Journal ArticleDOI
20 Sep 2002-Cell
TL;DR: Current structural and cell biological data suggest models for how integrins transmit signals between their extracellular ligand binding adhesion sites and their cytoplasmic domains, which link to the cytoskeleton and to signal transduction pathways.

8,275 citations

Journal ArticleDOI
14 Nov 1997-Cell
TL;DR: Mutation of the active site of caspase-9 attenuated the activation of cazase-3 and cellular apoptotic response in vivo, indicating that casp enzyme-9 is the most upstream member of the apoptotic protease cascade that is triggered by cytochrome c and dATP.

7,231 citations

Journal ArticleDOI
13 Dec 2001-Nature
TL;DR: The epidemic of type 2 diabetes and impaired glucose tolerance is one of the main causes of morbidity and mortality worldwide, and tissues such as muscle, fat and liver become less responsive or resistant to insulin.
Abstract: The epidemic of type 2 diabetes and impaired glucose tolerance is one of the main causes of morbidity and mortality worldwide. In both disorders, tissues such as muscle, fat and liver become less responsive or resistant to insulin. This state is also linked to other common health problems, such as obesity, polycystic ovarian disease, hyperlipidaemia, hypertension and atherosclerosis. The pathophysiology of insulin resistance involves a complex network of signalling pathways, activated by the insulin receptor, which regulates intermediary metabolism and its organization in cells. But recent studies have shown that numerous other hormones and signalling events attenuate insulin action, and are important in type 2 diabetes.

4,935 citations

Journal ArticleDOI
TL;DR: Recent progress has been made in understanding the details of the signaling pathways that regulate NF-kappaB activity, particularly those responding to the proinflammatory cytokines tumor necrosis factor-alpha and interleukin-1.
Abstract: NF-κB (nuclear factor-κB) is a collective name for inducible dimeric transcription factors composed of members of the Rel family of DNA-binding proteins that recognize a common sequence motif. NF-κ...

4,724 citations

Journal ArticleDOI
02 May 1997-Cell
TL;DR: This research was supported by grants from the National Institutes of Health (HL20948) and the Perot Family Foundation.

3,626 citations