Structural analysis of ricin and implications for inhibitor design

Robertus, Jon D.; Yan, Xinjian; Ernst, S.R.; Monzingo, A.F.; Worley, S. D.; Day, Philip J.; Hollis, Thomas; Svinth, M.

doi:10.1016/s0041-0101(96)00103-1

Cited by 23 publications

(14 citation statements)

References 27 publications

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“…Its toxicity is high, with a LD 50 to animals and humans in the µg kg −1 range (Robertus et al, 1996). Ricin was used to assassinate the Bulgarian journalist Georgi Markov in 1978, when less than 0.5 mg in a platinum/iridinium pellet was shot into his thigh, via the tip of an umbrella (Crompton and Gall, 1980).…”

Section: Introductionmentioning

confidence: 99%

“…The binding of the B-chain to the β-galactosides apparently triggers the endocytic uptake of the protein, and subsequent cleavage of the disulfide bond linking the two subunits (Montfort et al, 1987;Rivera-Sagredo et al, 1991;Morris and Wool, 1994). Once inside the cell, the ricin A-chain acts as a ribosomal RNA-N-glycosidase to remove an adenine residue from 28S rRNA, rendering it incapable of protein synthesis (Stirpe and Battelli, 1990;Robertus et al, 1996). By itself, the A-chain is not toxic, as in most circumstances it cannot enter the cell when separated from the B-chain.…”

Section: Introductionmentioning

confidence: 99%

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Monovalent and polyvalent carbohydrate inhibitors of ricin binding to a model of the cell-surface receptor

et al. 2006

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A selection of galactose and lactose analogues was evaluated for their potency in inhibiting the binding of ricin to immobilised asialofetuin, which is a model of the cell-surface receptor for ricin. The aim was to identify compounds that could be used as antagonists of ricin toxicity in vivo, and as more selective, and therefore safer, antitoxins. Although one of these analogues had been identified by molecular modelling in a previous study as a potentially potent inhibitor, it and the other carbohydrates studied were less effective than galactose and lactose themselves (I(50) = 1.39 and 0.74 mM, respectively). In an attempt to increase the potency of carbohydrate-based inhibitors, galactose was coupled to the surface of dendrimers. No synergistic interactions were observed from this multivalent approach. Encouraging results, however, were obtained with a self-assembled lyotropic mesophase gel containing novel synthetic galactose-based surfactants, which was able to sequester ricin from aqueous solution in a 2-phase system.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Monovalent and polyvalent carbohydrate inhibitors of ricin binding to a model of the cell-surface receptor

et al. 2006

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“…It showed clear contacts with the key active site residue, Arg162, even at the 2.5 cutoff in the ͉2F o Ϫ F c ͉ map. Synthetic pteridine derivatives have been identified as some of the most potent inhibitors of RIPs in vitro (41)(42)(43). Some of the pteridine derivatives are also abundant in plant vacuoles and are known to inhibit the enzymes involved in the purine metabolism (44).…”

Section: Resultsmentioning

confidence: 99%

“…The Arg 21 -Asp 23 comprises the kink region, and Trp 34 represents the conserved aromatic residue. The conserved polar residues involved in sugar binding are Asp 19 and Asn 43 . Their conformations are also similar to those found in the other RIPs.…”

Section: Resultsmentioning

confidence: 99%

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Crystal Structure of Himalayan Mistletoe Ribosome-inactivating Protein Reveals the Presence of a Natural Inhibitor and a New Functionally Active Sugar-binding Site

Mishra

Bilgrami

Sharma

et al. 2005

Journal of Biological Chemistry

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Ribosome-inactivating proteins (RIPs) are toxins involved in plant defense. How the plant prevents autotoxicity is not yet fully understood. The present study is the first structural evidence of a naturally inhibited form of RIP from a plant. Himalayan mistletoe RIP (HmRIP) was purified from Viscum album leaves and crystallized with lactose. The structure was determined by the molecular replacement method and refined at 2.8-Å resolution. The crystal structure revealed the presence of high quality non-protein electron density at the active site, into which a pteridine derivative (2-amino 4-isopropyl 6-carboxyl pteridine) was modeled. The carboxyl group of the ligand binds strongly with the key active site residue Arg 162 , nullifies the positive charge required for catalysis, and thereby acts as a natural inhibitor. Lectin subunits of RIPs have two active sugarbinding sites present in 1␣-and 2␥-subdomains. A third functionally active site has been identified in the 1␤-subdomain of HmRIP. The 1␤-site is active despite the absence of conserved polar sugar-binding residues. Loss of these residues is compensated by the following: (i) the presence of an extended site where the penultimate sugar also interacts with the protein; (ii) the interactions of galactose with the protein main chain carbonyl and amide nitrogen atoms; (iii) the presence of a well defined pocket encircled by four walls; and (iv) a favorable stacking of the galactose ring with Tyr 66 besides the conserved Phe 75 . The mode of sugar binding is also distinct at the 1␣ and 2␥ sugar-binding sites.

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Euphorbiaceae Juss.

and¹,

Tyrl²

2012

Toxic Plants of North America

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Structural analysis of ricin and implications for inhibitor design

Cited by 23 publications

References 27 publications

Monovalent and polyvalent carbohydrate inhibitors of ricin binding to a model of the cell-surface receptor

Monovalent and polyvalent carbohydrate inhibitors of ricin binding to a model of the cell-surface receptor

Crystal Structure of Himalayan Mistletoe Ribosome-inactivating Protein Reveals the Presence of a Natural Inhibitor and a New Functionally Active Sugar-binding Site

Euphorbiaceae Juss.

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