Crystal structure and novel recognition motif of Rho ADP-ribosylating C3 exoenzyme from Clostridium botulinum: structural insights for recognition specificity and catalysis

Han, Seungil; Arvai, A.S.; Clancy, Sheila; Tainer, John A.

doi:10.1006/jmbi.2000.4292

Cited by 138 publications

(173 citation statements)

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“…C3bot1 was the first C3-like exoenzyme, which was successfully crystallized by Han et al (2001). The overall structure of the toxin has a mixed α, β-fold: a central β-sandwich, which is formed by a perpendicular packing of a five-stranded β-sheet against a three stranded β-sheet surrounding the NAD-binding pocket (Fig.…”

Section: Structural Analysis Of C3-like Exoenzymesmentioning

confidence: 99%

“…Together they form the so-called STS motif (in C3stau transferases an ST motif), which connects strand β3 with the PN loop and maintains the reaction cavity. This central cleft of C3bot is terminated on one side by a so called ARTT loop (Han et al 2001), a double turn motif consisting of 10 residues. The ARTT loop was proposed as part of the active site center and is conserved in other ADP-ribosyltransferases (e.g., actin-modifying Bacillus cereus VIP 2).…”

Section: Structural Analysis Of C3-like Exoenzymesmentioning

confidence: 99%

“…It contains the invariant catalytic glutamate C3bot E174 as well as C3bot Q172 and C3bot F169 residues, which are necessary for the activity of C3-like transferases. In their model for the ADP-ribosylation of Rho by C3bot, Tainer and coworkers predicted that C3 recognizes its substrate mainly via the ARTT loop (Han et al 2001). In that context C3bot F169 was proposed to contribute to the binding of Rho via a hydrophobic interaction with a patch of Rho (RhoA V38,F39,V43 ), whereas C3bot Q172 was proposed to interact with Rho N41 , the acceptor for the ADP-ribose moiety.…”

Section: Structural Analysis Of C3-like Exoenzymesmentioning

confidence: 99%

“…4). The conformational change of C3bot Q172 is thought to be important for correctly positioning Rho into the ternary Rho-NAD-C3 complex (Han et al 2001;Ménétrey et al 2002). Additionally, the catalytic glutamate C3bot E174 was found to interact with O-2′-hydroxyl ribose of the nicotinamide ribose, which suggested the stabilization of an oxocarbenium transition state during the ADP-ribose transfer.…”

Section: Structural Analysis Of C3-like Exoenzymesmentioning

confidence: 99%

“…C3bot in complex with NAD (pdb code 1GZF) is displayed as ribbon plot (left). Secondary structure elements are color-coded (α-helices, blue, β-sheets, orange) and labeled according to Han et al (2001). ARTT loop and PN loop, which enclose the active site are shown in yellow, with the catalytic residues C3bot Q172 and C3bot E174 as stick models; the newly defined helix-loop-helix motif (HLH motif, green) mediates the non-enzymatic interaction of C3bot with Ral.…”

Section: Structural Analysis Of C3-like Exoenzymesmentioning

confidence: 99%

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C3 exoenzymes, novel insights into structure and action of Rho-ADP-ribosylating toxins

Vogelsgesang

Pautsch

Aktories

2006

Naunyn-Schmied Arch Pharmacol

100

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The family of C3-like exoenzymes comprises seven bacterial ADP-ribosyltransferases of different origin. The common hallmark of these exoenzymes is the selective N-ADP-ribosylation of the low molecular mass GTPbinding proteins RhoA, B, and C and inhibition of signal pathways controlled by Rho GTPases. Therefore, C3-like exoenzymes were applied as pharmacological tools for analyses of cellular functions of Rho protein in numerous studies. Recent structural and functional analyses of C3-like exoenzymes provide detailed information on the molecular mechanisms and functional consequences of ADP-ribosylation catalyzed by these toxins. More recently additional non-enzymatic actions of C3-like ADP-ribosyltransferases have been identified showing that C3 transferases from Clostridium botulinum and Clostridium limosum form a GDI-like complex with the Ras-like low molecular mass GTPase Ral without ADP-ribosylation. These results add novel information on the molecular mode of action(s) of C3-like exoenzymes and are discussed in this review.

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Section: Structural Analysis Of C3-like Exoenzymesmentioning

confidence: 99%

Section: Structural Analysis Of C3-like Exoenzymesmentioning

confidence: 99%

Section: Structural Analysis Of C3-like Exoenzymesmentioning

confidence: 99%

Section: Structural Analysis Of C3-like Exoenzymesmentioning

confidence: 99%

Section: Structural Analysis Of C3-like Exoenzymesmentioning

confidence: 99%

See 3 more Smart Citations

C3 exoenzymes, novel insights into structure and action of Rho-ADP-ribosylating toxins

Vogelsgesang

Pautsch

Aktories

2006

Naunyn-Schmied Arch Pharmacol

100

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Development of Second‐Generation Small‐Molecule RhoA Inhibitors with Enhanced Water Solubility, Tissue Potency, and Significant in vivo Efficacy

Ma¹,

Deng²,

Li³

et al. 2014

ChemMedChem

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RhoA, a member of the Rho GTPases, is involved in a variety of cellular functions and could be a suitable therapeutic target for the treatment of cardiovascular diseases. However, few small-molecule RhoA inhibitors have been reported. Based on our previously reported lead compounds, 32 new 2-substituted quinoline (or quinoxaline) derivatives were synthesized and tested in biological assays. Six compounds showed high RhoA inhibitory activities, with IC50 values of 1.17-1.84 μM. Among these, (E)-3-(3-(ethyl(quinolin-2-yl)amino)phenyl)acrylic acid (26 b) and (E)-3-(3-(butyl(quinolin-2-yl)amino)phenyl)acrylic acid (26 d) demonstrated noticeable vasorelaxation effects against phenylephrine-induced contraction in thoracic aorta artery rings, and compound 26 b had good water solubility and showed significant in vivo efficacy, which was similar to that of 5-(1,4-diazepane-1-sulfonyl)isoquinoline (fasudil) in a subarachnoid hemorrhage-cardiovascular model. To the best of our knowledge, compound 26 b is the first example of a small- molecule RhoA inhibitor with potent in vivo efficacy, which could serve as a good lead for designing cardiovascular agents.

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Refined crystallographic structure of Pseudomonas aeruginosa exotoxin A and its implications for the molecular mechanism of toxicity 1 1Edited by D. Rees

Wedekind

Trame

Dorywalska

et al. 2001

Journal of Molecular Biology

100

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Crystal structure and novel recognition motif of Rho ADP-ribosylating C3 exoenzyme from Clostridium botulinum: structural insights for recognition specificity and catalysis

Cited by 138 publications

References 48 publications

C3 exoenzymes, novel insights into structure and action of Rho-ADP-ribosylating toxins

C3 exoenzymes, novel insights into structure and action of Rho-ADP-ribosylating toxins

Development of Second‐Generation Small‐Molecule RhoA Inhibitors with Enhanced Water Solubility, Tissue Potency, and Significant in vivo Efficacy

Refined crystallographic structure of Pseudomonas aeruginosa exotoxin A and its implications for the molecular mechanism of toxicity 1 1Edited by D. Rees

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