3cwm › Citations

Preventing serpin aggregation: the molecular mechanism of citrate action upon antitrypsin unfolding.

Pearce MC, Morton CJ, Feil SC, Hansen G, Adams JJ, Parker MW, Bottomley SP
Protein Sci 17 2127-33 (2008)
Related entries: 2qug, 3cwl

Cited: 20 times
EuropePMC logo PMID: 18780818

Abstract

The aggregation of antitrypsin into polymers is one of the causes of neonatal hepatitis, cirrhosis, and emphysema. A similar reaction resulting in disease can occur in other human serpins, and collectively they are known as the serpinopathies. One possible therapeutic strategy involves inhibiting the conformational changes involved in antitrypsin aggregation. The citrate ion has previously been shown to prevent antitrypsin aggregation and maintain the protein in an active conformation; its mechanism of action, however, is unknown. Here we demonstrate that the citrate ion prevents the initial misfolding of the native state to a polymerogenic intermediate in a concentration-dependent manner. Furthermore, we have solved the crystal structure of citrate bound to antitrypsin and show that a single citrate molecule binds in a pocket between the A and B beta-sheets, a region known to be important in maintaining antitrypsin stability.

Reviews - 3cwm mentioned but not cited (1)

  1. Peptides and peptidomimetics as therapeutic agents for Covid-19. Dahal A, Sonju JJ, Kousoulas KG, Jois SD. Pept Sci (Hoboken) 114 e24245 (2022)

Articles - 3cwm mentioned but not cited (7)

  1. Alpha-1 antitrypsin inhibits TMPRSS2 protease activity and SARS-CoV-2 infection. Wettstein L, Weil T, Conzelmann C, Müller JA, Groß R, Hirschenberger M, Seidel A, Klute S, Zech F, Prelli Bozzo C, Preising N, Fois G, Lochbaum R, Knaff PM, Mailänder V, Ständker L, Thal DR, Schumann C, Stenger S, Kleger A, Lochnit G, Mayer B, Ruiz-Blanco YB, Hoffmann M, Sparrer KMJ, Pöhlmann S, Sanchez-Garcia E, Kirchhoff F, Frick M, Münch J. Nat Commun 12 1726 (2021)
  2. Preventing serpin aggregation: the molecular mechanism of citrate action upon antitrypsin unfolding. Pearce MC, Morton CJ, Feil SC, Hansen G, Adams JJ, Parker MW, Bottomley SP. Protein Sci. 17 2127-2133 (2008)
  3. In silico assessment of potential druggable pockets on the surface of α1-antitrypsin conformers. Patschull AO, Gooptu B, Ashford P, Daviter T, Nobeli I. PLoS ONE 7 e36612 (2012)
  4. Discovery of an inhibitor of Z-alpha1 antitrypsin polymerization. Berthelier V, Harris JB, Estenson KN, Baudry J. PLoS ONE 10 e0126256 (2015)
  5. Proteomic and molecular dynamic investigations of PTM-induced structural fluctuations in breast and ovarian cancer. Tikhonov D, Kulikova L, Kopylov AT, Rudnev V, Stepanov A, Malsagova K, Izotov A, Kulikov D, Zulkarnaev A, Enikeev D, Potoldykova N, Kaysheva AL. Sci Rep 11 19318 (2021)
  6. CHARMM-GUI Glycan Modeler for modeling and simulation of carbohydrates and glycoconjugates. Park SJ, Lee J, Qi Y, Kern NR, Lee HS, Jo S, Joung I, Joo K, Lee J, Im W. Glycobiology 29 320-331 (2019)
  7. Meditation-induced bloodborne factors as an adjuvant treatment to COVID-19 disease. Zuniga-Hertz JP, Chitteti R, Dispenza J, Cuomo R, Bonds JA, Kopp EL, Simpson S, Okerblom J, Maurya S, Rana BK, Miyonahara A, Niesman IR, Maree J, Belza G, Hamilton HD, Stanton C, Gonzalez DJ, Poirier MA, Moeller-Bertram T, Patel HH. Brain Behav Immun Health 32 100675 (2023)


Reviews citing this publication (1)

  1. Therapeutic targeting of misfolding and conformational change in α1-antitrypsin deficiency. Nyon MP, Gooptu B. Future Med Chem 6 1047-1065 (2014)

Articles citing this publication (11)

  1. Structural and functional characterization of a highly specific serpin in the insect innate immunity. Park SH, Jiang R, Piao S, Zhang B, Kim EH, Kwon HM, Jin XL, Lee BL, Ha NC. J. Biol. Chem. 286 1567-1575 (2011)
  2. Aberrant disulphide bonding contributes to the ER retention of alpha1-antitrypsin deficiency variants. Ronzoni R, Berardelli R, Medicina D, Sitia R, Gooptu B, Fra AM. Hum. Mol. Genet. 25 642-650 (2016)
  3. Development of a small molecule that corrects misfolding and increases secretion of Z α1 -antitrypsin. Lomas DA, Irving JA, Arico-Muendel C, Belyanskaya S, Brewster A, Brown M, Chung CW, Dave H, Denis A, Dodic N, Dossang A, Eddershaw P, Klimaszewska D, Haq I, Holmes DS, Hutchinson JP, Jagger AM, Jakhria T, Jigorel E, Liddle J, Lind K, Marciniak SJ, Messer J, Neu M, Olszewski A, Ordonez A, Ronzoni R, Rowedder J, Rüdiger M, Skinner S, Smith KJ, Terry R, Trottet L, Uings I, Wilson S, Zhu Z, Pearce AC. EMBO Mol Med 13 e13167 (2021)
  4. Therapeutic target-site variability in α1-antitrypsin characterized at high resolution. Patschull AO, Segu L, Nyon MP, Lomas DA, Nobeli I, Barrett TE, Gooptu B. Acta Crystallogr. Sect. F Struct. Biol. Cryst. Commun. 67 1492-1497 (2011)
  5. Inhibition of unfolding and aggregation of lens protein human gamma D crystallin by sodium citrate. Goulet DR, Knee KM, King JA. Exp. Eye Res. 93 371-381 (2011)
  6. Smoothing a rugged protein folding landscape by sequence-based redesign. Porebski BT, Keleher S, Hollins JJ, Nickson AA, Marijanovic EM, Borg NA, Costa MG, Pearce MA, Dai W, Zhu L, Irving JA, Hoke DE, Kass I, Whisstock JC, Bottomley SP, Webb GI, McGowan S, Buckle AM. Sci Rep 6 33958 (2016)
  7. Interactions of alpha1-proteinase inhibitor with small ligands of therapeutic potential: binding with retinoic acid. Karnaukhova E. Amino Acids 38 1011-1020 (2010)
  8. Serpin functions in host-pathogen interactions. Bao J, Pan G, Poncz M, Wei J, Ran M, Zhou Z. PeerJ 6 e4557 (2018)
  9. A Novel Small Molecule Inhibits Intrahepatocellular Accumulation of Z-Variant Alpha 1-Antitrypsin In Vitro and In Vivo. Zhang X, Pham K, Li D, Schutte RJ, Gonzalo DH, Zhang P, Oshins R, Tan W, Brantly M, Liu C, Ostrov DA. Cells 8 (2019)
  10. Crystal structure of cleaved vaspin (serpinA12). Pippel J, Kuettner EB, Ulbricht D, Daberger J, Schultz S, Heiker JT, Sträter N. Biol. Chem. 397 111-123 (2016)
  11. Functional characterization of a SNP (F51S) found in human alpha 1-antitrypsin. Trinh HN, Jang SH, Lee C. Mol Genet Genomic Med 7 e819 (2019)


Quick links