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Home / Equine Research Bank / Mol Immunol / Crystal structure of equine serum albumin in complex with ce...
Molecular immunology2016; 71; 143-151; doi: 10.1016/j.molimm.2016.02.003

Crystal structure of equine serum albumin in complex with cetirizine reveals a novel drug binding site.

Abstract: Serum albumin (SA) is the main transporter of drugs in mammalian blood plasma. Here, we report the first crystal structure of equine serum albumin (ESA) in complex with antihistamine drug cetirizine at a resolution of 2.1Å. Cetirizine is bound in two sites--a novel drug binding site (CBS1) and the fatty acid binding site 6 (CBS2). Both sites differ from those that have been proposed in multiple reports based on equilibrium dialysis and fluorescence studies for mammalian albumins as cetirizine binding sites. We show that the residues forming the binding pockets in ESA are highly conserved in human serum albumin (HSA), and suggest that binding of cetirizine to HSA will be similar. In support of that hypothesis, we show that the dissociation constants for cetirizine binding to CBS2 in ESA and HSA are identical using tryptophan fluorescence quenching. Presence of lysine and arginine residues that have been previously reported to undergo nonenzymatic glycosylation in CBS1 and CBS2 suggests that cetirizine transport in patients with diabetes could be altered. A review of all available SA structures from the PDB shows that in addition to the novel drug binding site we present here (CBS1), there are two pockets on SA capable of binding drugs that do not overlap with fatty acid binding sites and have not been discussed in published reviews.
Copyright © 2016 Elsevier Ltd. All rights reserved.
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Publication Date: 2016-02-17 PubMed ID: 26896718PubMed Central: PMC4800003DOI: 10.1016/j.molimm.2016.02.003Google Scholar: Lookup
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Summary

This research summary has been generated with artificial intelligence and may contain errors and omissions. Refer to the original study to confirm details provided. Submit correction.

The researchers have uncovered the first crystal structure of horse serum albumin (ESA) when combined with an antihistamine drug called cetirizine. They discovered a new location where the drug attaches itself, providing fresh insights on how drugs are transported in blood plasma. The study also indicates that this binding method could change in diabetes patients.

Identification of a New Drug Binding Site

  • This research is focused on serum albumin (SA), a protein found in mammalian blood plasma that’s vital for transporting drugs throughout the body. The novel feature of this study is the discovery of cetirizine, an antihistamine drug, binding to a previously unknown site on equine serum albumin (ESA), which is the horse equivalent of human serum albumin.
  • The researchers were able to map out the crystal structure of ESA when it’s combined with cetirizine. This enabled them to identify not only the new drug binding site (CBS1), but another site (CBS2) associated with fatty acid binding. Both these sites were different from previously theorized cetirizine binding sites.

Binding Sites and Human Serum Albumin

  • The study analyzed the pockets within ESA where cetirizine binds, noting that the amino acid residues forming these pockets are largely conserved (retained through evolution due to their importance) in human serum albumin (HSA). Hence, it’s suggested that the binding of cetirizine will be similar in human SA.
  • The supporting evidence for this hypothesis is given by the similar dissociation constants (a measure of the strength of the chemical bond) for cetirizine in both ESA and HSA. The same was tested using a technique called tryptophan fluorescence quenching.

Implications for Diabetes Patients

  • The researchers highlighted the presence of two types of residues, lysine and arginine, in both CBS1 and CBS2. Both of these residues have been reported to undergo a process called nonenzymatic glycosylation, where a sugar molecule attaches to a protein without the aid of an enzyme.
  • This process is considerably more frequent in patients with diabetes. The researchers, therefore, suggest that this could potentially alter how cetirizine is transported in the bodies of these patients, indicating the need for further exploration in this area.

Expanded Review of SA Structures

  • In a broader context, the research team reviewed all available SA structures present in the Protein Data Bank (PDB). This review illustrated that there are, in fact, two additional sites on SA that can accommodate drug binding and were not overlapping with fatty acid binding sites.
  • These sites have not been discussed in previous reviews, highlighting again the continuing and evolving nature of drug binding site research.

Cite This Article

APA
Handing KB, Shabalin IG, Szlachta K, Majorek KA, Minor W. (2016). Crystal structure of equine serum albumin in complex with cetirizine reveals a novel drug binding site. Mol Immunol, 71, 143-151. https://doi.org/10.1016/j.molimm.2016.02.003

Publication

Molecular immunology
ISSN: 1872-9142
NlmUniqueID: 7905289
Country: England
Language: English
Volume: 71
Pages: 143-151
PII: S0161-5890(16)30016-5

Researcher Affiliations

Handing, Katarzyna B
  • Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, VA 22908-0736, USA; New York Structural Genomics Research Consortium (NYSGRC), USA.
Shabalin, Ivan G
  • Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, VA 22908-0736, USA; New York Structural Genomics Research Consortium (NYSGRC), USA.
Szlachta, Karol
  • Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, VA 22908-0736, USA; Faculty of Physics, Warsaw University of Technology, 00-662 Warszawa, Poland.
Majorek, Karolina A
  • Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, VA 22908-0736, USA; New York Structural Genomics Research Consortium (NYSGRC), USA.
Minor, Wladek
  • Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, VA 22908-0736, USA; New York Structural Genomics Research Consortium (NYSGRC), USA. Electronic address: wladek@iwonka.med.virginia.edu.

MeSH Terms

  • Amino Acid Sequence
  • Animals
  • Binding Sites / physiology
  • Cetirizine / chemistry
  • Cetirizine / metabolism
  • Crystallography, X-Ray
  • Histamine H1 Antagonists, Non-Sedating / chemistry
  • Histamine H1 Antagonists, Non-Sedating / metabolism
  • Horses
  • Humans
  • Models, Molecular
  • Molecular Sequence Data
  • Protein Structure, Quaternary
  • Serum Albumin / chemistry
  • Serum Albumin / metabolism

Grant Funding

  • GM053163 / NIGMS NIH HHS
  • GM094662 / NIGMS NIH HHS
  • R01 GM053163 / NIGMS NIH HHS
  • HG008424 / NHGRI NIH HHS
  • U01 HG008424 / NHGRI NIH HHS
  • U54 GM094662 / NIGMS NIH HHS

References

This article includes 37 references
  1. Anguizola J, Matsuda R, Barnaby OS, Hoy KS, Wa C, DeBolt E, Koke M, Hage DS. Review: Glycation of human serum albumin.. Clin Chim Acta 2013 Oct 21;425:64-76.
    doi: 10.1016/j.cca.2013.07.013pmc: PMC3795802pubmed: 23891854google scholar: lookup
  2. Barnaby OS, Cerny RL, Clarke W, Hage DS. Comparison of modification sites formed on human serum albumin at various stages of glycation.. Clin Chim Acta 2011 Jan 30;412(3-4):277-85.
    doi: 10.1016/j.cca.2010.10.018pmc: PMC3053033pubmed: 21034726google scholar: lookup
  3. Bern M, Sand KM, Nilsen J, Sandlie I, Andersen JT. The role of albumin receptors in regulation of albumin homeostasis: Implications for drug delivery.. J Control Release 2015 Aug 10;211:144-62.
    doi: 10.1016/j.jconrel.2015.06.006pubmed: 26055641google scholar: lookup
  4. Bhattacharya AA, Curry S, Franks NP. Binding of the general anesthetics propofol and halothane to human serum albumin. High resolution crystal structures.. J Biol Chem 2000 Dec 8;275(49):38731-8.
    doi: 10.1074/jbc.M005460200pubmed: 10940303google scholar: lookup
  5. Bhattacharya AA, Grüne T, Curry S. Crystallographic analysis reveals common modes of binding of medium and long-chain fatty acids to human serum albumin.. J Mol Biol 2000 Nov 10;303(5):721-32.
    doi: 10.1006/jmbi.2000.4158pubmed: 11061971google scholar: lookup
  6. Bree F, Thiault L, Gautiers G, Benedetti MS, Baltes E, Rihoux JP, Tillement JP. Blood distribution of levocetirizine, a new non-sedating histamine H1-receptor antagonist, in humans.. Fundam Clin Pharmacol 2002 Dec;16(6):471-8.
    doi: 10.1046/j.1472-8206.2002.00111.xpubmed: 12685505google scholar: lookup
  7. Chen VB, Arendall WB 3rd, Headd JJ, Keedy DA, Immormino RM, Kapral GJ, Murray LW, Richardson JS, Richardson DC. MolProbity: all-atom structure validation for macromolecular crystallography.. Acta Crystallogr D Biol Crystallogr 2010 Jan;66(Pt 1):12-21.
    doi: 10.1107/S0907444909042073pmc: PMC2803126pubmed: 20057044google scholar: lookup
  8. Chruszcz M, Mikolajczak K, Mank N, Majorek KA, Porebski PJ, Minor W. Serum albumins-unusual allergens.. Biochim Biophys Acta 2013 Dec;1830(12):5375-81.
    doi: 10.1016/j.bbagen.2013.06.016pmc: PMC4419372pubmed: 23811341google scholar: lookup
  9. Curry S. Lessons from the crystallographic analysis of small molecule binding to human serum albumin.. Drug Metab Pharmacokinet 2009;24(4):342-57.
    doi: 10.2133/dmpk.24.342pubmed: 19745561google scholar: lookup
  10. Ehrenberg M, Cronvall E, Rigler R. Fluorescence of proteins interacting with nucleic acids. Correction for light absorption.. FEBS Lett 1971 Nov 1;18(2):199-203.
    doi: 10.1016/0014-5793(71)80444-1pubmed: 11946120google scholar: lookup
  11. Eisenberg D, Schwarz E, Komaromy M, Wall R. Analysis of membrane and surface protein sequences with the hydrophobic moment plot.. J Mol Biol 1984 Oct 15;179(1):125-42.
    doi: 10.1016/0022-2836(84)90309-7pubmed: 6502707google scholar: lookup
  12. Emsley P, Cowtan K. Coot: model-building tools for molecular graphics.. Acta Crystallogr D Biol Crystallogr 2004 Dec;60(Pt 12 Pt 1):2126-32.
    doi: 10.1107/S0907444904019158pubmed: 15572765google scholar: lookup
  13. Gadgil HS, Bondarenko PV, Treuheit MJ, Ren D. Screening and sequencing of glycated proteins by neutral loss scan LC/MS/MS method.. Anal Chem 2007 Aug 1;79(15):5991-9.
    doi: 10.1021/ac070619kpubmed: 17571855google scholar: lookup
  14. Ghuman J, Zunszain PA, Petitpas I, Bhattacharya AA, Otagiri M, Curry S. Structural basis of the drug-binding specificity of human serum albumin.. J Mol Biol 2005 Oct 14;353(1):38-52.
    doi: 10.1016/j.jmb.2005.07.075pubmed: 16169013google scholar: lookup
  15. Hegde AH, Sandhya B, Kalanur SS, Seetharamappa J. Binding mechanism of bioactive cetirizine hydrochloride to sudlow’s site i of serum albumins. J. Solution Chem. 2011;40:182–197.
    doi: 10.1007/s10953-010-9640-8google scholar: lookup
  16. Holm L, Rosenström P. Dali server: conservation mapping in 3D.. Nucleic Acids Res 2010 Jul;38(Web Server issue):W545-9.
    doi: 10.1093/nar/gkq366pmc: PMC2896194pubmed: 20457744google scholar: lookup
  17. Katoh K, Standley DM. MAFFT multiple sequence alignment software version 7: improvements in performance and usability.. Mol Biol Evol 2013 Apr;30(4):772-80.
    doi: 10.1093/molbev/mst010pmc: PMC3603318pubmed: 23329690google scholar: lookup
  18. Liu X, Du Y, Sun W, Kou J, Yu B. Study on the interaction of levocetirizine dihydrochloride with human serum albumin by molecular spectroscopy.. Spectrochim Acta A Mol Biomol Spectrosc 2009 Dec;74(5):1189-96.
    doi: 10.1016/j.saa.2009.09.033pubmed: 19857990google scholar: lookup
  19. Mansoor SE, Dewitt MA, Farrens DL. Distance mapping in proteins using fluorescence spectroscopy: the tryptophan-induced quenching (TrIQ) method.. Biochemistry 2010 Nov 16;49(45):9722-31.
    doi: 10.1016/j.biotechadv.2011.08.021.Secretedpmc: PMC3938424pubmed: 20886836google scholar: lookup
  20. Minor W, Cymborowski M, Otwinowski Z, Chruszcz M. HKL-3000: the integration of data reduction and structure solution--from diffraction images to an initial model in minutes.. Acta Crystallogr D Biol Crystallogr 2006 Aug;62(Pt 8):859-66.
    doi: 10.1107/S0907444906019949pubmed: 16855301google scholar: lookup
  21. Murshudov GN, Skubák P, Lebedev AA, Pannu NS, Steiner RA, Nicholls RA, Winn MD, Long F, Vagin AA. REFMAC5 for the refinement of macromolecular crystal structures.. Acta Crystallogr D Biol Crystallogr 2011 Apr;67(Pt 4):355-67.
    doi: 10.1107/S0907444911001314pmc: PMC3069751pubmed: 21460454google scholar: lookup
  22. Otwinowski Z, Minor W. Processing of X-ray diffraction data collected in oscillation mode.. Methods Enzymol 1997;276:307-26.
    doi: 10.1016/s0076-6879(97)76066-xpubmed: 27754618google scholar: lookup
  23. Pagliara A, Testa B, Carrupt PA, Jolliet P, Morin C, Morin D, Urien S, Tillement JP, Rihoux JP. Molecular properties and pharmacokinetic behavior of cetirizine, a zwitterionic H1-receptor antagonist.. J Med Chem 1998 Mar 12;41(6):853-63.
    doi: 10.1021/jm9704311pubmed: 9526560google scholar: lookup
  24. Painter J, Merritt EA. TLSMD web server for the generation of multi-group TLS models. J. Appl. Crystallogr. 2006;39:109–111.
    doi: 10.1107/S0021889805038987google scholar: lookup
  25. Peters TJ. All About Albumin: Biochemistry, Genetics, and Medical Applications. .
  26. Read RJ, Adams PD, Arendall WB 3rd, Brunger AT, Emsley P, Joosten RP, Kleywegt GJ, Krissinel EB, Lütteke T, Otwinowski Z, Perrakis A, Richardson JS, Sheffler WH, Smith JL, Tickle IJ, Vriend G, Zwart PH. A new generation of crystallographic validation tools for the protein data bank.. Structure 2011 Oct 12;19(10):1395-412.
    doi: 10.1016/j.str.2011.08.006pmc: PMC3195755pubmed: 22000512google scholar: lookup
  27. Ruiz-Cabello F, Erill S. Abnormal serum protein binding of acidic drugs in diabetes mellitus.. Clin Pharmacol Ther 1984 Nov;36(5):691-5.
    doi: 10.1038/clpt.1984.241pubmed: 6488690google scholar: lookup
  28. Sekula B, Zielinski K, Bujacz A. Crystallographic studies of the complexes of bovine and equine serum albumin with 3,5-diiodosalicylic acid.. Int J Biol Macromol 2013 Sep;60:316-24.
    doi: 10.1016/j.ijbiomac.2013.06.004pubmed: 23769932google scholar: lookup
  29. Spector AA, John K, Fletcher JE. Binding of long-chain fatty acids to bovine serum albumin.. J Lipid Res 1969 Jan;10(1):56-67.
    doi: 10.1021/bi00793a011pubmed: 5773785google scholar: lookup
  30. Sudlow G, Birkett DJ, Wade DN. Further characterization of specific drug binding sites on human serum albumin.. Mol Pharmacol 1976 Nov;12(6):1052-61.
    pubmed: 1004490
  31. Sudlow G, Birkett DJ, Wade DN. The characterization of two specific drug binding sites on human serum albumin.. Mol Pharmacol 1975 Nov;11(6):824-32.
    pubmed: 1207674
  32. Sugio S, Kashima A, Mochizuki S, Noda M, Kobayashi K. Crystal structure of human serum albumin at 2.5 A resolution.. Protein Eng 1999 Jun;12(6):439-46.
    pubmed: 10388840doi: 10.1093/protein/12.6.439google scholar: lookup
  33. Tillement JP, Testa B, Brée F. Compared pharmacological characteristics in humans of racemic cetirizine and levocetirizine, two histamine H1-receptor antagonists.. Biochem Pharmacol 2003 Oct 1;66(7):1123-6.
    doi: 10.1016/S0006-2952(03)00558-6pubmed: 14505791google scholar: lookup
  34. Vagin A, Teplyakov A. MOLREP: an Automated Program for Molecular Replacement. J. Appl. Crystallogr. 1997;30:1022–1025.
    doi: 10.1107/S0021889897006766google scholar: lookup
  35. Van De Weert M, Stella L. Fluorescence quenching and ligand binding: A critical discussion of a popular methodology. J. Mol. Struct. 2011;998:145–150.
    doi: 10.1016/j.molstruc.2011.05.023google scholar: lookup
  36. Wang ZM, Ho JX, Ruble JR, Rose J, Rüker F, Ellenburg M, Murphy R, Click J, Soistman E, Wilkerson L, Carter DC. Structural studies of several clinically important oncology drugs in complex with human serum albumin.. Biochim Biophys Acta 2013 Dec;1830(12):5356-74.
    doi: 10.1016/j.bbagen.2013.06.032pubmed: 23838380google scholar: lookup
  37. Winn MD, Ballard CC, Cowtan KD, Dodson EJ, Emsley P, Evans PR, Keegan RM, Krissinel EB, Leslie AG, McCoy A, McNicholas SJ, Murshudov GN, Pannu NS, Potterton EA, Powell HR, Read RJ, Vagin A, Wilson KS. Overview of the CCP4 suite and current developments.. Acta Crystallogr D Biol Crystallogr 2011 Apr;67(Pt 4):235-42.
    doi: 10.1107/S0907444910045749pmc: PMC3069738pubmed: 21460441google scholar: lookup

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