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Structural analysis of thermostabilizing mutations of cocaine esterase.

Narasimhan D, Nance MR, Gao D, Ko MC, Macdonald J, Tamburi P, Yoon D, Landry DM, Woods JH, Zhan CG, Tesmer JJ, Sunahara RK
Protein Eng Des Sel 23 537-47 (2010)
Related entries: 3i2f, 3i2g, 3i2h, 3i2i, 3i2j

Cited: 30 times
EuropePMC logo PMID: 20436035

Abstract

Cocaine is considered to be the most addictive of all substances of abuse and mediates its effects by inhibiting monoamine transporters, primarily the dopamine transporters. There are currently no small molecules that can be used to combat its toxic and addictive properties, in part because of the difficulty of developing compounds that inhibit cocaine binding without having intrinsic effects on dopamine transport. Most of the effective cocaine inhibitors also display addictive properties. We have recently reported the use of cocaine esterase (CocE) to accelerate the removal of systemic cocaine and to prevent cocaine-induced lethality. However, wild-type CocE is relatively unstable at physiological temperatures (tau(1/2) approximately 13 min at 37 degrees C), presenting challenges for its development as a viable therapeutic agent. We applied computational approaches to predict mutations to stabilize CocE and showed that several of these have increased stability both in vitro and in vivo, with the most efficacious mutant (T172R/G173Q) extending half-life up to 370 min. Here we present novel X-ray crystallographic data on these mutants that provide a plausible model for the observed enhanced stability. We also more extensively characterize the previously reported variants and report on a new stabilizing mutant, L169K. The improved stability of these engineered CocE enzymes will have a profound influence on the use of this protein to combat cocaine-induced toxicity and addiction in humans.

Reviews - 3i2k mentioned but not cited (1)

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Articles - 3i2k mentioned but not cited (2)

  1. Structural analysis of thermostabilizing mutations of cocaine esterase. Narasimhan D, Nance MR, Gao D, Ko MC, Macdonald J, Tamburi P, Yoon D, Landry DM, Woods JH, Zhan CG, Tesmer JJ, Sunahara RK. Protein Eng Des Sel 23 537-547 (2010)
  2. The acid-base-nucleophile catalytic triad in ABH-fold enzymes is coordinated by a set of structural elements. Denesyuk A, Dimitriou PS, Johnson MS, Nakayama T, Denessiouk K. PLoS One 15 e0229376 (2020)


Reviews citing this publication (3)

  1. Accelerating cocaine metabolism as an approach to the treatment of cocaine abuse and toxicity. Schindler CW, Goldberg SR. Future Med Chem 4 163-175 (2012)
  2. Computational design of protein-ligand interfaces: potential in therapeutic development. Morin A, Meiler J, Mizoue LS. Trends Biotechnol 29 159-166 (2011)
  3. Empirical comparison and analysis of machine learning-based predictors for predicting and analyzing of thermophilic proteins. Charoenkwan P, Schaduangrat N, Hasan MM, Moni MA, Lió P, Shoombuatong W. EXCLI J 21 554-570 (2022)

Articles citing this publication (24)

  1. A thermostable Cas9 with increased lifetime in human plasma. Harrington LB, Paez-Espino D, Staahl BT, Chen JS, Ma E, Kyrpides NC, Doudna JA. Nat Commun 8 1424 (2017)
  2. Design, preparation, and characterization of high-activity mutants of human butyrylcholinesterase specific for detoxification of cocaine. Xue L, Ko MC, Tong M, Yang W, Hou S, Fang L, Liu J, Zheng F, Woods JH, Tai HH, Zhan CG. Mol Pharmacol 79 290-297 (2011)
  3. Biocatalytic and structural properties of a highly engineered halohydrin dehalogenase. Schallmey M, Floor RJ, Hauer B, Breuer M, Jekel PA, Wijma HJ, Dijkstra BW, Janssen DB. Chembiochem 14 870-881 (2013)
  4. Enzyme-therapy approaches for the treatment of drug overdose and addiction. Zheng F, Zhan CG. Future Med Chem 3 9-13 (2011)
  5. Long-lasting effects of a PEGylated mutant cocaine esterase (CocE) on the reinforcing and discriminative stimulus effects of cocaine in rats. Collins GT, Narasimhan D, Cunningham AR, Zaks ME, Nichols J, Ko MC, Sunahara RK, Woods JH. Neuropsychopharmacology 37 1092-1103 (2012)
  6. Amelioration of the cardiovascular effects of cocaine in rhesus monkeys by a long-acting mutant form of cocaine esterase. Collins GT, Carey KA, Narasimhan D, Nichols J, Berlin AA, Lukacs NW, Sunahara RK, Woods JH, Ko MC. Neuropsychopharmacology 36 1047-1059 (2011)
  7. Rational design, preparation, and characterization of a therapeutic enzyme mutant with improved stability and function for cocaine detoxification. Fang L, Chow KM, Hou S, Xue L, Chen X, Rodgers DW, Zheng F, Zhan CG. ACS Chem Biol 9 1764-1772 (2014)
  8. Cell permeable cocaine esterases constructed by chemical conjugation and genetic recombination. Lee TY, Park YS, Garcia GA, Sunahara RK, Woods JH, Yang VC. Mol Pharm 9 1361-1373 (2012)
  9. Characterization of a thermostable Cas13 enzyme for one-pot detection of SARS-CoV-2. Mahas A, Marsic T, Lopez-Portillo Masson M, Wang Q, Aman R, Zheng C, Ali Z, Alsanea M, Al-Qahtani A, Ghanem B, Alhamlan F, Mahfouz M. Proc Natl Acad Sci U S A 119 e2118260119 (2022)
  10. Reaction mechanism for cocaine esterase-catalyzed hydrolyses of (+)- and (-)-cocaine: unexpected common rate-determining step. Liu J, Zhao X, Yang W, Zhan CG. J Phys Chem B 115 5017-5025 (2011)
  11. Subunit stabilization and polyethylene glycolation of cocaine esterase improves in vivo residence time. Narasimhan D, Collins GT, Nance MR, Nichols J, Edwald E, Chan J, Ko MC, Woods JH, Tesmer JJ, Sunahara RK. Mol Pharmacol 80 1056-1065 (2011)
  12. Computational design of a thermostable mutant of cocaine esterase via molecular dynamics simulations. Huang X, Gao D, Zhan CG. Org Biomol Chem 9 4138-4143 (2011)
  13. A novel sequence-based predictor for identifying and characterizing thermophilic proteins using estimated propensity scores of dipeptides. Charoenkwan P, Chotpatiwetchkul W, Lee VS, Nantasenamat C, Shoombuatong W. Sci Rep 11 23782 (2021)
  14. Effects of a long-acting mutant bacterial cocaine esterase on acute cocaine toxicity in rats. Collins GT, Zaks ME, Cunningham AR, St Clair C, Nichols J, Narasimhan D, Ko MC, Sunahara RK, Woods JH. Drug Alcohol Depend 118 158-165 (2011)
  15. Repeated administration of a mutant cocaine esterase: effects on plasma cocaine levels, cocaine-induced cardiovascular activity, and immune responses in rhesus monkeys. Collins GT, Brim RL, Noon KR, Narasimhan D, Lukacs NW, Sunahara RK, Woods JH, Ko MC. J Pharmacol Exp Ther 342 205-213 (2012)
  16. The ability of bacterial cocaine esterase to hydrolyze cocaine metabolites and their simultaneous quantification using high-performance liquid chromatography-tandem mass spectrometry. Brim RL, Noon KR, Collins GT, Nichols J, Narasimhan D, Sunahara RK, Woods JH. Mol Pharmacol 80 1119-1127 (2011)
  17. Cocaine esterase-cocaine binding process and the free energy profiles by molecular dynamics and potential of mean force simulations. Huang X, Zhao X, Zheng F, Zhan CG. J Phys Chem B 116 3361-3368 (2012)
  18. Bacterial DNA induces the formation of heat-resistant disease-associated proteins in human plasma. Tetz V, Tetz G. Sci Rep 9 17995 (2019)
  19. Evaluation of the hydrolytic activity of a long-acting mutant bacterial cocaine in the presence of commonly co-administered drugs. Brim RL, Noon KR, Nichols J, Narasimhan D, Woods JH, Sunahara RK. Drug Alcohol Depend 119 224-228 (2011)
  20. QSE: A new 3-D solvent exposure measure for the analysis of protein structure. Li P, Pok G, Jung KS, Shon HS, Ryu KH. Proteomics 11 3793-3801 (2011)
  21. The fate of bacterial cocaine esterase (CocE): an in vivo study of CocE-mediated cocaine hydrolysis, CocE pharmacokinetics, and CocE elimination. Brim RL, Noon KR, Collins GT, Stein A, Nichols J, Narasimhan D, Ko MC, Woods JH, Sunahara RK. J Pharmacol Exp Ther 340 83-95 (2012)
  22. Sulfhydryl-specific PEGylation of phosphotriesterase cysteine mutants for organophosphate detoxification. Daffu GK, Lopez P, Katz F, Vinogradov M, Zhan CG, Landry DW, Macdonald J. Protein Eng Des Sel 28 501-506 (2015)
  23. Free energy profiles of cocaine esterase-cocaine binding process by molecular dynamics and potential of mean force simulations. Zhang Y, Huang X, Han K, Zheng F, Zhan CG. Chem Biol Interact 259 142-147 (2016)
  24. Homologous Pairs of Low and High Temperature Originating Proteins Spanning the Known Prokaryotic Universe. Komp E, Alanzi HN, Francis R, Vuong C, Roberts L, Mosallanejad A, Beck DAC. Sci Data 10 682 (2023)


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