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. 1999 Oct;8(10):2072–2084. doi: 10.1110/ps.8.10.2072

Barrel structures in proteins: automatic identification and classification including a sequence analysis of TIM barrels.

N Nagano 1, E G Hutchinson 1, J M Thornton 1
PMCID: PMC2144152  PMID: 10548053

Abstract

Automated methods for identifying and characterizing regular beta-barrels from coordinate data have been developed to analyze and classify various kinds of barrel structures based on geometric parameters such as the barrel strand number (n) and shear number (S). In total, we find 1,316 barrels in the January 1998 release of Protein Data Bank. Of 1,316 barrels, 1,277 barrels had an even shear number, corresponding to 50 nonhomologous families. The (beta alpha)8 triose phosphate isomerase (TIM) barrel (n = 8, S = 8) fold has the largest number of apparently nonhomologous entries, 16, although the trypsin like antiparallel (n = 6, S = 8) barrels (representing only three families) are the most common with 527 barrels. Of all the protein families that exhibit barrel structures, 68% are found to be various kinds of enzymes, the remainder being binding proteins and transport membrane proteins. In addition, the layers of side chains, which form the cores of barrels with S = n and S = 2n, are also analyzed. More sophisticated methods were developed for detecting TIM barrels specifically, including consideration of the amino acid propensities for the side chains that form the layers. We found that the residues on the outside of the eight stranded parallel beta-barrel, buried by the alpha-helices, are much more hydrophobic than the residues inside the barrel.

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Selected References

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  1. Banner D. W., Bloomer A. c., Petsko G. A., Phillips D. C., Wilson I. A. Atomic coordinates for triose phosphate isomerase from chicken muscle. Biochem Biophys Res Commun. 1976 Sep 7;72(1):146–155. doi: 10.1016/0006-291x(76)90972-4. [DOI] [PubMed] [Google Scholar]
  2. Bellamy H. D., Lim L. W., Mathews F. S., Dunham W. R. Studies of crystalline trimethylamine dehydrogenase in three oxidation states and in the presence of substrate and inhibitor. J Biol Chem. 1989 Jul 15;264(20):11887–11892. [PubMed] [Google Scholar]
  3. Benning M. M., Kuo J. M., Raushel F. M., Holden H. M. Three-dimensional structure of phosphotriesterase: an enzyme capable of detoxifying organophosphate nerve agents. Biochemistry. 1994 Dec 20;33(50):15001–15007. doi: 10.1021/bi00254a008. [DOI] [PubMed] [Google Scholar]
  4. Bernstein F. C., Koetzle T. F., Williams G. J., Meyer E. F., Jr, Brice M. D., Rodgers J. R., Kennard O., Shimanouchi T., Tasumi M. The Protein Data Bank: a computer-based archival file for macromolecular structures. J Mol Biol. 1977 May 25;112(3):535–542. doi: 10.1016/s0022-2836(77)80200-3. [DOI] [PubMed] [Google Scholar]
  5. Blaber M., DiSalvo J., Thomas K. A. X-ray crystal structure of human acidic fibroblast growth factor. Biochemistry. 1996 Feb 20;35(7):2086–2094. doi: 10.1021/bi9521755. [DOI] [PubMed] [Google Scholar]
  6. Brady R. L., Brzozowski A. M., Derewenda Z. S., Dodson E. J., Dodson G. G. Solution of the structure of Aspergillus niger acid alpha-amylase by combined molecular replacement and multiple isomorphous replacement methods. Acta Crystallogr B. 1991 Aug 1;47(Pt 4):527–535. doi: 10.1107/s0108768191001908. [DOI] [PubMed] [Google Scholar]
  7. Chan A. W., Hutchinson E. G., Harris D., Thornton J. M. Identification, classification, and analysis of beta-bulges in proteins. Protein Sci. 1993 Oct;2(10):1574–1590. doi: 10.1002/pro.5560021004. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Collyer C. A., Henrick K., Blow D. M. Mechanism for aldose-ketose interconversion by D-xylose isomerase involving ring opening followed by a 1,2-hydride shift. J Mol Biol. 1990 Mar 5;212(1):211–235. doi: 10.1016/0022-2836(90)90316-E. [DOI] [PubMed] [Google Scholar]
  9. Cutfield S. M., Dodson E. J., Anderson B. F., Moody P. C., Marshall C. J., Sullivan P. A., Cutfield J. F. The crystal structure of a major secreted aspartic proteinase from Candida albicans in complexes with two inhibitors. Structure. 1995 Nov 15;3(11):1261–1271. doi: 10.1016/s0969-2126(01)00261-1. [DOI] [PubMed] [Google Scholar]
  10. Ducros V., Czjzek M., Belaich A., Gaudin C., Fierobe H. P., Belaich J. P., Davies G. J., Haser R. Crystal structure of the catalytic domain of a bacterial cellulase belonging to family 5. Structure. 1995 Sep 15;3(9):939–949. doi: 10.1016/S0969-2126(01)00228-3. [DOI] [PubMed] [Google Scholar]
  11. Fox K. M., Karplus P. A. Old yellow enzyme at 2 A resolution: overall structure, ligand binding, and comparison with related flavoproteins. Structure. 1994 Nov 15;2(11):1089–1105. [PubMed] [Google Scholar]
  12. Goldman A., Ollis D. L., Steitz T. A. Crystal structure of muconate lactonizing enzyme at 3 A resolution. J Mol Biol. 1987 Mar 5;194(1):143–153. doi: 10.1016/0022-2836(87)90723-6. [DOI] [PubMed] [Google Scholar]
  13. Harris G. W., Jenkins J. A., Connerton I., Pickersgill R. W. Refined crystal structure of the catalytic domain of xylanase A from Pseudomonas fluorescens at 1.8 A resolution. Acta Crystallogr D Biol Crystallogr. 1996 Mar 1;52(Pt 2):393–401. doi: 10.1107/S0907444995013540. [DOI] [PubMed] [Google Scholar]
  14. Hennig M., Schlesier B., Dauter Z., Pfeffer S., Betzel C., Höhne W. E., Wilson K. S. A TIM barrel protein without enzymatic activity? Crystal-structure of narbonin at 1.8 A resolution. FEBS Lett. 1992 Jul 13;306(1):80–84. doi: 10.1016/0014-5793(92)80842-5. [DOI] [PubMed] [Google Scholar]
  15. Hoier H., Schlömann M., Hammer A., Glusker J. P., Carrell H. L., Goldman A., Stezowski J. J., Heinemann U. Crystal structure of chloromuconate cycloisomerase from Alcaligenes eutrophus JMP134 (pJP4) at 3 A resolution. Acta Crystallogr D Biol Crystallogr. 1994 Jan 1;50(Pt 1):75–84. doi: 10.1107/S090744499300900X. [DOI] [PubMed] [Google Scholar]
  16. Hutchinson E. G., Thornton J. M. HERA--a program to draw schematic diagrams of protein secondary structures. Proteins. 1990;8(3):203–212. doi: 10.1002/prot.340080303. [DOI] [PubMed] [Google Scholar]
  17. Hutchinson E. G., Thornton J. M. PROMOTIF--a program to identify and analyze structural motifs in proteins. Protein Sci. 1996 Feb;5(2):212–220. doi: 10.1002/pro.5560050204. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Hyde C. C., Ahmed S. A., Padlan E. A., Miles E. W., Davies D. R. Three-dimensional structure of the tryptophan synthase alpha 2 beta 2 multienzyme complex from Salmonella typhimurium. J Biol Chem. 1988 Nov 25;263(33):17857–17871. [PubMed] [Google Scholar]
  19. Jabri E., Karplus P. A. Structures of the Klebsiella aerogenes urease apoenzyme and two active-site mutants. Biochemistry. 1996 Aug 20;35(33):10616–10626. doi: 10.1021/bi960424z. [DOI] [PubMed] [Google Scholar]
  20. Jia J., Schörken U., Lindqvist Y., Sprenger G. A., Schneider G. Crystal structure of the reduced Schiff-base intermediate complex of transaldolase B from Escherichia coli: mechanistic implications for class I aldolases. Protein Sci. 1997 Jan;6(1):119–124. doi: 10.1002/pro.5560060113. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Kabsch W., Sander C. Dictionary of protein secondary structure: pattern recognition of hydrogen-bonded and geometrical features. Biopolymers. 1983 Dec;22(12):2577–2637. doi: 10.1002/bip.360221211. [DOI] [PubMed] [Google Scholar]
  22. Kawashima T., Berthet-Colominas C., Wulff M., Cusack S., Leberman R. The structure of the Escherichia coli EF-Tu.EF-Ts complex at 2.5 A resolution. Nature. 1996 Feb 8;379(6565):511–518. doi: 10.1038/379511a0. [DOI] [PubMed] [Google Scholar]
  23. Klein C., Schulz G. E. Structure of cyclodextrin glycosyltransferase refined at 2.0 A resolution. J Mol Biol. 1991 Feb 20;217(4):737–750. doi: 10.1016/0022-2836(91)90530-j. [DOI] [PubMed] [Google Scholar]
  24. Koivula A., Reinikainen T., Ruohonen L., Valkeajärvi A., Claeyssens M., Teleman O., Kleywegt G. J., Szardenings M., Rouvinen J., Jones T. A. The active site of Trichoderma reesei cellobiohydrolase II: the role of tyrosine 169. Protein Eng. 1996 Aug;9(8):691–699. doi: 10.1093/protein/9.8.691. [DOI] [PubMed] [Google Scholar]
  25. Leesong M., Henderson B. S., Gillig J. R., Schwab J. M., Smith J. L. Structure of a dehydratase-isomerase from the bacterial pathway for biosynthesis of unsaturated fatty acids: two catalytic activities in one active site. Structure. 1996 Mar 15;4(3):253–264. doi: 10.1016/s0969-2126(96)00030-5. [DOI] [PubMed] [Google Scholar]
  26. Lesk A. M., Brändén C. I., Chothia C. Structural principles of alpha/beta barrel proteins: the packing of the interior of the sheet. Proteins. 1989;5(2):139–148. doi: 10.1002/prot.340050208. [DOI] [PubMed] [Google Scholar]
  27. Li de la Sierra I., Pernot L., Prangé T., Saludjian P., Schiltz M., Fourme R., Padrón G. Molecular structure of the lipoamide dehydrogenase domain of a surface antigen from Neisseria meningitidis. J Mol Biol. 1997 May 30;269(1):129–141. doi: 10.1006/jmbi.1997.1009. [DOI] [PubMed] [Google Scholar]
  28. Liu W. M. Shear numbers of protein beta-barrels: definition refinements and statistics. J Mol Biol. 1998 Jan 30;275(4):541–545. doi: 10.1006/jmbi.1997.1501. [DOI] [PubMed] [Google Scholar]
  29. Mancia F., Keep N. H., Nakagawa A., Leadlay P. F., McSweeney S., Rasmussen B., Bösecke P., Diat O., Evans P. R. How coenzyme B12 radicals are generated: the crystal structure of methylmalonyl-coenzyme A mutase at 2 A resolution. Structure. 1996 Mar 15;4(3):339–350. doi: 10.1016/s0969-2126(96)00037-8. [DOI] [PubMed] [Google Scholar]
  30. Martin A. C., Orengo C. A., Hutchinson E. G., Jones S., Karmirantzou M., Laskowski R. A., Mitchell J. B., Taroni C., Thornton J. M. Protein folds and functions. Structure. 1998 Jul 15;6(7):875–884. doi: 10.1016/s0969-2126(98)00089-6. [DOI] [PubMed] [Google Scholar]
  31. Mattevi A., Obmolova G., Kalk K. H., van Berkel W. J., Hol W. G. Three-dimensional structure of lipoamide dehydrogenase from Pseudomonas fluorescens at 2.8 A resolution. Analysis of redox and thermostability properties. J Mol Biol. 1993 Apr 20;230(4):1200–1215. doi: 10.1006/jmbi.1993.1236. [DOI] [PubMed] [Google Scholar]
  32. McLachlan A. D. Gene duplications in the structural evolution of chymotrypsin. J Mol Biol. 1979 Feb 15;128(1):49–79. doi: 10.1016/0022-2836(79)90308-5. [DOI] [PubMed] [Google Scholar]
  33. McRee D. E., Redford S. M., Getzoff E. D., Lepock J. R., Hallewell R. A., Tainer J. A. Changes in crystallographic structure and thermostability of a Cu,Zn superoxide dismutase mutant resulting from the removal of a buried cysteine. J Biol Chem. 1990 Aug 25;265(24):14234–14241. doi: 10.2210/pdb3sod/pdb. [DOI] [PubMed] [Google Scholar]
  34. Merritt E. A., Sarfaty S., Chang T. T., Palmer L. M., Jobling M. G., Holmes R. K., Hol W. G. Surprising leads for a cholera toxin receptor-binding antagonist: crystallographic studies of CTB mutants. Structure. 1995 Jun 15;3(6):561–570. doi: 10.1016/s0969-2126(01)00190-3. [DOI] [PubMed] [Google Scholar]
  35. Meyer J. E., Hofnung M., Schulz G. E. Structure of maltoporin from Salmonella typhimurium ligated with a nitrophenyl-maltotrioside. J Mol Biol. 1997 Mar 7;266(4):761–775. doi: 10.1006/jmbi.1996.0823. [DOI] [PubMed] [Google Scholar]
  36. Mikami B., Sato M., Shibata T., Hirose M., Aibara S., Katsube Y., Morita Y. Three-dimensional structure of soybean beta-amylase determined at 3.0 A resolution: preliminary chain tracing of the complex with alpha-cyclodextrin. J Biochem. 1992 Oct;112(4):541–546. doi: 10.1093/oxfordjournals.jbchem.a123935. [DOI] [PubMed] [Google Scholar]
  37. Murzin A. G., Lesk A. M., Chothia C. Principles determining the structure of beta-sheet barrels in proteins. I. A theoretical analysis. J Mol Biol. 1994 Mar 11;236(5):1369–1381. doi: 10.1016/0022-2836(94)90064-7. [DOI] [PubMed] [Google Scholar]
  38. Murzin A. G., Lesk A. M., Chothia C. Principles determining the structure of beta-sheet barrels in proteins. II. The observed structures. J Mol Biol. 1994 Mar 11;236(5):1382–1400. doi: 10.1016/0022-2836(94)90065-5. [DOI] [PubMed] [Google Scholar]
  39. Neidhart D. J., Howell P. L., Petsko G. A., Powers V. M., Li R. S., Kenyon G. L., Gerlt J. A. Mechanism of the reaction catalyzed by mandelate racemase. 2. Crystal structure of mandelate racemase at 2.5-A resolution: identification of the active site and possible catalytic residues. Biochemistry. 1991 Sep 24;30(38):9264–9273. doi: 10.1021/bi00102a019. [DOI] [PubMed] [Google Scholar]
  40. Orengo C. A., Michie A. D., Jones S., Jones D. T., Swindells M. B., Thornton J. M. CATH--a hierarchic classification of protein domain structures. Structure. 1997 Aug 15;5(8):1093–1108. doi: 10.1016/s0969-2126(97)00260-8. [DOI] [PubMed] [Google Scholar]
  41. Parge H. E., Hallewell R. A., Tainer J. A. Atomic structures of wild-type and thermostable mutant recombinant human Cu,Zn superoxide dismutase. Proc Natl Acad Sci U S A. 1992 Jul 1;89(13):6109–6113. doi: 10.1073/pnas.89.13.6109. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Perrakis A., Tews I., Dauter Z., Oppenheim A. B., Chet I., Wilson K. S., Vorgias C. E. Crystal structure of a bacterial chitinase at 2.3 A resolution. Structure. 1994 Dec 15;2(12):1169–1180. doi: 10.1016/s0969-2126(94)00119-7. [DOI] [PubMed] [Google Scholar]
  43. Raghunathan S., Ricard C. S., Lohman T. M., Waksman G. Crystal structure of the homo-tetrameric DNA binding domain of Escherichia coli single-stranded DNA-binding protein determined by multiwavelength x-ray diffraction on the selenomethionyl protein at 2.9-A resolution. Proc Natl Acad Sci U S A. 1997 Jun 24;94(13):6652–6657. doi: 10.1073/pnas.94.13.6652. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Reardon D., Farber G. K. The structure and evolution of alpha/beta barrel proteins. FASEB J. 1995 Apr;9(7):497–503. doi: 10.1096/fasebj.9.7.7737457. [DOI] [PubMed] [Google Scholar]
  45. Rognan D., Scapozza L., Folkers G., Daser A. Molecular dynamics simulation of MHC-peptide complexes as a tool for predicting potential T cell epitopes. Biochemistry. 1994 Sep 27;33(38):11476–11485. doi: 10.1021/bi00204a009. [DOI] [PubMed] [Google Scholar]
  46. Schneider G., Lindqvist Y., Brändén C. I., Lorimer G. Three-dimensional structure of ribulose-1,5-bisphosphate carboxylase/oxygenase from Rhodospirillum rubrum at 2.9 A resolution. EMBO J. 1986 Dec 20;5(13):3409–3415. doi: 10.1002/j.1460-2075.1986.tb04662.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Stein P. E., Boodhoo A., Armstrong G. D., Cockle S. A., Klein M. H., Read R. J. The crystal structure of pertussis toxin. Structure. 1994 Jan 15;2(1):45–57. doi: 10.1016/s0969-2126(00)00007-1. [DOI] [PubMed] [Google Scholar]
  48. Van Roey P., Rao V., Plummer T. H., Jr, Tarentino A. L. Crystal structure of endo-beta-N-acetylglucosaminidase F1, an alpha/beta-barrel enzyme adapted for a complex substrate. Biochemistry. 1994 Nov 29;33(47):13989–13996. doi: 10.1021/bi00251a005. [DOI] [PubMed] [Google Scholar]
  49. Varghese J. N., Garrett T. P., Colman P. M., Chen L., Høj P. B., Fincher G. B. Three-dimensional structures of two plant beta-glucan endohydrolases with distinct substrate specificities. Proc Natl Acad Sci U S A. 1994 Mar 29;91(7):2785–2789. doi: 10.1073/pnas.91.7.2785. [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. Wilson D. K., Rudolph F. B., Quiocho F. A. Atomic structure of adenosine deaminase complexed with a transition-state analog: understanding catalysis and immunodeficiency mutations. Science. 1991 May 31;252(5010):1278–1284. doi: 10.1126/science.1925539. [DOI] [PubMed] [Google Scholar]
  51. van den Akker F., Sarfaty S., Twiddy E. M., Connell T. D., Holmes R. K., Hol W. G. Crystal structure of a new heat-labile enterotoxin, LT-IIb. Structure. 1996 Jun 15;4(6):665–678. doi: 10.1016/s0969-2126(96)00073-1. [DOI] [PubMed] [Google Scholar]

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