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Structural characterization of the cyclic cystine ladder motif of θ-defensins.

Conibear AC, Rosengren KJ, Harvey PJ, Craik DJ
Biochemistry 51 9718-26 (2012)
Related entries: 2lye, 2lzi

Cited: 39 times
EuropePMC logo PMID: 23148585

Abstract

The θ-defensins are, to date, the only known ribosomally synthesized cyclic peptides in mammals, and they have promising antimicrobial bioactivities. The characteristic structural motif of the θ-defensins is the cyclic cystine ladder, comprising a cyclic peptide backbone and three parallel disulfide bonds. In contrast to the cyclic cystine knot, which characterizes the plant cyclotides, the cyclic cystine ladder has not been as well described as a structural motif. Here we report the solution structures and nuclear magnetic resonance relaxation properties in aqueous solution of three representative θ-defensins from different species. Our data suggest that the θ-defensins are more rigid and structurally defined than previously thought. In addition, all three θ-defensins were found to self-associate in aqueous solution in a concentration-dependent and reversible manner, a property that might have a role in their mechanism of action. The structural definition of the θ-defensins and the cyclic cystine ladder will help to guide exploitation of these molecules as structural frameworks for the design of peptide drugs.

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  3. Targeting and inactivation of bacterial toxins by human defensins. Kudryashova E, Seveau SM, Kudryashov DS. Biol Chem 398 1069-1085 (2017)
  4. Host Defense Peptides as Templates for Antifungal Drug Development. Basso V, Tran DQ, Ouellette AJ, Selsted ME. J Fungi (Basel) 6 E241 (2020)
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  1. New Modalities for Challenging Targets in Drug Discovery. Valeur E, Guéret SM, Adihou H, Gopalakrishnan R, Lemurell M, Waldmann H, Grossmann TN, Plowright AT. Angew Chem Int Ed Engl 56 10294-10323 (2017)
  2. Defensins in innate immunity. Zhao L, Lu W. Curr Opin Hematol 21 37-42 (2014)
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  4. Defensins, lectins, mucins, and secretory immunoglobulin A: microbe-binding biomolecules that contribute to mucosal immunity in the human gut. Chairatana P, Nolan EM. Crit Rev Biochem Mol Biol 52 45-56 (2017)
  5. Tumor cell membrane-targeting cationic antimicrobial peptides: novel insights into mechanisms of action and therapeutic prospects. Baxter AA, Lay FT, Poon IKH, Kvansakul M, Hulett MD. Cell Mol Life Sci 74 3809-3825 (2017)
  6. Discovery and optimization of peptide macrocycles. White AM, Craik DJ. Expert Opin Drug Discov 11 1151-1163 (2016)
  7. Antimicrobial Mechanisms and Clinical Application Prospects of Antimicrobial Peptides. Li X, Zuo S, Wang B, Zhang K, Wang Y. Molecules 27 2675 (2022)
  8. Classes, Databases, and Prediction Methods of Pharmaceutically and Commercially Important Cystine-Stabilized Peptides. Islam SMA, Kearney CM, Baker E. Toxins (Basel) 10 E251 (2018)
  9. Native and Engineered Cyclic Disulfide-Rich Peptides as Drug Leads. Tyler TJ, Durek T, Craik DJ. Molecules 28 3189 (2023)

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  2. Structure-Based Design of Hepatitis C Virus Vaccines That Elicit Neutralizing Antibody Responses to a Conserved Epitope. Pierce BG, Boucher EN, Piepenbrink KH, Ejemel M, Rapp CA, Thomas WD, Sundberg EJ, Weng Z, Wang Y. J Virol 91 e01032-17 (2017)
  3. The cyclic cystine ladder in θ-defensins is important for structure and stability, but not antibacterial activity. Conibear AC, Rosengren KJ, Daly NL, Henriques ST, Craik DJ. J Biol Chem 288 10830-10840 (2013)
  4. Identification and Characterization of ProTx-III [μ-TRTX-Tp1a], a New Voltage-Gated Sodium Channel Inhibitor from Venom of the Tarantula Thrixopelma pruriens. Cardoso FC, Dekan Z, Rosengren KJ, Erickson A, Vetter I, Deuis JR, Herzig V, Alewood PF, King GF, Lewis RJ. Mol Pharmacol 88 291-303 (2015)
  5. Low cationicity is important for systemic in vivo efficacy of database-derived peptides against drug-resistant Gram-positive pathogens. Mishra B, Lakshmaiah Narayana J, Lushnikova T, Wang X, Wang G. Proc Natl Acad Sci U S A 116 13517-13522 (2019)
  6. Interaction of Tarantula Venom Peptide ProTx-II with Lipid Membranes Is a Prerequisite for Its Inhibition of Human Voltage-gated Sodium Channel NaV1.7. Henriques ST, Deplazes E, Lawrence N, Cheneval O, Chaousis S, Inserra M, Thongyoo P, King GF, Mark AE, Vetter I, Craik DJ, Schroeder CI. J Biol Chem 291 17049-17065 (2016)
  7. Semienzymatic cyclization of disulfide-rich peptides using Sortase A. Jia X, Kwon S, Wang CA, Huang YH, Chan LY, Tan CC, Rosengren KJ, Mulvenna JP, Schroeder CI, Craik DJ. J Biol Chem 289 6627-6638 (2014)
  8. The cyclic cystine ladder of theta-defensins as a stable, bifunctional scaffold: A proof-of-concept study using the integrin-binding RGD motif. Conibear AC, Bochen A, Rosengren KJ, Stupar P, Wang C, Kessler H, Craik DJ. Chembiochem 15 451-459 (2014)
  9. Design and synthesis of truncated EGF-A peptides that restore LDL-R recycling in the presence of PCSK9 in vitro. Schroeder CI, Swedberg JE, Withka JM, Rosengren KJ, Akcan M, Clayton DJ, Daly NL, Cheneval O, Borzilleri KA, Griffor M, Stock I, Colless B, Walsh P, Sunderland P, Reyes A, Dullea R, Ammirati M, Liu S, McClure KF, Tu M, Bhattacharya SK, Liras S, Price DA, Craik DJ. Chem Biol 21 284-294 (2014)
  10. Approaches to the stabilization of bioactive epitopes by grafting and peptide cyclization. Conibear AC, Chaousis S, Durek T, Rosengren KJ, Craik DJ, Schroeder CI. Biopolymers 106 89-100 (2016)
  11. Species-Specific Functional Regions of the Green Alga Gamete Fusion Protein HAP2 Revealed by Structural Studies. Baquero E, Fedry J, Legrand P, Krey T, Rey FA. Structure 27 113-124.e4 (2019)
  12. The π Configuration of the WWW Motif of a Short Trp-Rich Peptide Is Critical for Targeting Bacterial Membranes, Disrupting Preformed Biofilms, and Killing Methicillin-Resistant Staphylococcus aureus. Zarena D, Mishra B, Lushnikova T, Wang F, Wang G. Biochemistry 56 4039-4043 (2017)
  13. Efficient enzymatic cyclization of an inhibitory cystine knot-containing peptide. Kwon S, Bosmans F, Kaas Q, Cheneval O, Conibear AC, Rosengren KJ, Wang CK, Schroeder CI, Craik DJ. Biotechnol Bioeng 113 2202-2212 (2016)
  14. Suppression and resolution of autoimmune arthritis by rhesus θ-defensin-1, an immunomodulatory macrocyclic peptide. Schaal JB, Tran DQ, Subramanian A, Patel R, Laragione T, Roberts KD, Trinh K, Tongaonkar P, Tran PA, Minond D, Fields GB, Beringer P, Ouellette AJ, Gulko PS, Selsted ME. PLoS One 12 e0187868 (2017)
  15. Novel analgesic ω-conotoxins from the vermivorous cone snail Conus moncuri provide new insights into the evolution of conopeptides. Sousa SR, McArthur JR, Brust A, Bhola RF, Rosengren KJ, Ragnarsson L, Dutertre S, Alewood PF, Christie MJ, Adams DJ, Vetter I, Lewis RJ. Sci Rep 8 13397 (2018)
  16. Retrocyclins neutralize bacterial toxins by potentiating their unfolding. Kudryashova E, Seveau S, Lu W, Kudryashov DS. Biochem J 467 311-320 (2015)
  17. Truncated Glucagon-like Peptide-1 and Exendin-4 α-Conotoxin pl14a Peptide Chimeras Maintain Potency and α-Helicity and Reveal Interactions Vital for cAMP Signaling in Vitro. Swedberg JE, Schroeder CI, Mitchell JM, Fairlie DP, Edmonds DJ, Griffith DA, Ruggeri RB, Derksen DR, Loria PM, Price DA, Liras S, Craik DJ. J Biol Chem 291 15778-15787 (2016)
  18. Insights into the molecular flexibility of θ-defensins by NMR relaxation analysis. Conibear AC, Wang CK, Bi T, Rosengren KJ, Camarero JA, Craik DJ. J Phys Chem B 118 14257-14266 (2014)
  19. Thermodynamic instability of viral proteins is a pathogen-associated molecular pattern targeted by human defensins. Kudryashova E, Koneru PC, Kvaratskhelia M, Strömstedt AA, Lu W, Kudryashov DS. Sci Rep 6 32499 (2016)
  20. Mechanism through Which Retrocyclin Targets Flavivirus Multiplication. Jia X, Guo J, Yuan W, Sun L, Liu Y, Zhou M, Xiao G, Lu W, Garzino-Demo A, Wang W. J Virol 95 e0056021 (2021)


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