Journal of Molecular Evolution

, Volume 30, Issue 1, pp 43–59 | Cite as

Molecular anatomy: Phyletic relationships derived from three-dimensional structures of proteins

  • Mark S. Johnson
  • Michael J. Sutcliffe
  • Tom L. Blundell


A distance measure that reflects the dissimilarity among structures has been developed on the basis of the three-dimensional structures of similar proteins, this being totally independent of sequence in the sense that only the relative spatial positions of mainchain alpha-carbon atoms need be known. This procedure leads to phyletic relationships that are in general correlated with the sequence phylogenies based on residue type. Such relationships among known protein three-dimensional structures are also a useful aid to their classification and selection in knowledge-based modeling using homologous structures. We have applied this approach to six homologous sets of proteins: immunoglobulin fragments, globins, cytochromesc, serine proteinases, eye-lens gamma crystallins, and dinucleotide-binding domains.

Key words

Phyletic trees from x-ray crystal structures Sequences Globins Cytochromes Immunoglobulins Serine proteinases Eye-lens gamma crystallins Dinucleotide-binding proteins 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Ambler RP, Meyer TE, Kamen MD, Schichman SA, Sawyer L (1981) A reassessment of the structure ofParacoccus cytochromec-550. J Mol Biol 147:351–356CrossRefPubMedGoogle Scholar
  2. Argos P, Hanei M, Wilson JM, Kelley WN (1983) A possible nucleotide-binding domain in the tertiary fold of phosphoribosyltransferases. J Biol Chem 25:6450–6457Google Scholar
  3. Arutyunyan ÉG, Kuranova IP, Vainshtein BK, Steigemann W (1980) X-ray structural investigation of leghemoglobin VI. Structure of acetate-ferrileghemoglobin at a resolution of 2.0 A. Krystallografiya 25:80–103Google Scholar
  4. Bajaj M, Blundell T (1984) Evolution and the tertiary structure of proteins. Annu Rev Biophys Bioeng 13:453–492CrossRefPubMedGoogle Scholar
  5. Baldwin JM (1980) The structure of human carbonmonoxy haemoglobin at 2.7 Å resolution. J Mol Biol 136:103–128CrossRefPubMedGoogle Scholar
  6. Barker WC, Ketcham LK, Dayhoff MO (1978) Immunoglobulins. In: Dayhoff MO (ed) Atlas of protein sequence and structure, vol 5, suppl 3. National Biomedical Research Foundation. Washington DC, pp 197–227Google Scholar
  7. Bernstein FC, Koetzle TF, Williams GJB, Meyer eF, Brice MD, Rodgers JR, Kennard O, Shimanouchi T, Tasumi M (1977) The Protein Data Bank: a computer based archival file for macromolecular structures. J Mol Biol 112:535–542PubMedGoogle Scholar
  8. Birktoft JJ, Banaszak LJ (1983) The presence of a histidineaspartic acid pair in the active site 2-hydroxyacid dehydrogenases. X-ray refinement of cytoplasmic malate dehydrogenase. J Bio. Chem 258:472–482Google Scholar
  9. Blundell T, Lindley P, Miller L, Moss D, Slingsby C, Tickle I, Turnell B, Wistow G (1981) The molecular structure and stability of the eye lens: x-ray analysis of gamma-crystallin II. Nature 289:771–777PubMedGoogle Scholar
  10. Blundell T, Carney D, Gardner S, Hayes F, Howlin B, Hubbard T, Overington J, Singh DA, Sibanda BL, Sutcliffe M (1988a) Knowledge-based protein modelling and design. Eur J Biochem 172:513–520CrossRefPubMedGoogle Scholar
  11. Blundell TL, Elliot G, Gardner SP, Hubbard T, Islam I, Johnson M, Mantafounis D, Murray-Rust P, Overington J, Pitts JE, Šali A, Sibanda BL, Singh J, Sternberg MJE, Sutcliffe MJ, Thornton JM, Travers P (1988b) Protein engineering and design. Phil Trans R Soc Lond, series B (in press)Google Scholar
  12. Bode W, Chen Z, Bartels K, Kutzbach C, Schmidt-Kastner G, Bartunik H (1983) Refined 2 Å x-ray crystal structure of porcine pancreatic kallikrein A, a specific trypsin-like serine proteinase. Crystallization, structure determination, crystallographic refinement, structure and its comparison with bovine trypsin. J Mol Biol 164:237–282CrossRefPubMedGoogle Scholar
  13. Bolton W, Perutz MF (1970) Three dimensional Fourier synthesis of horse deoxyhaemoglobin at 2.8 Å resolution. Nature 228:551–552PubMedGoogle Scholar
  14. Brändén C-I, Schneider G, Lindqvist Y, Andersson I, Knight S, Lorimer G (1987) Structural and evolutionary aspects of the key enzymes in photorespiration; RuBisCO and glycolate oxidase. Cold Spring Harbor Symp Quant Biol LII:491–498Google Scholar
  15. Buehner M, Ford GC, Moras D, Olsen KW, Rossmann MG (1973) D-glyceraldehyde-3-phosphate dehydrogenase: three dimensional structure and evolutionary significance. Proc Natl Acad Sci USA 70:3052–3054PubMedGoogle Scholar
  16. Carter DC, Melis KA, O'Donnell SE, Burgess BK, Furey WF, Wang B-C, Stout CD (1985) Crystal structure ofAzotobacter cytochromec 5 at 2.5 Å resolution. J Mol Biol 184:279–295CrossRefPubMedGoogle Scholar
  17. Cederlund E, Lindqvist Y, Söderlund G, Brändén C-I, Jörnvall H (1988) Primary structure of glycolate oxidase from spinach. Eur J Biochem 173:523–530PubMedGoogle Scholar
  18. Chothia, C, Lesk AM (1982) Evolution of proteins formed by β-sheets: I. Plastocyanin and azurin. J Mol Biol 160:309–323CrossRefPubMedGoogle Scholar
  19. Chothia C, Lesk AM (1986) The relation between the divergence of sequence and structure in proteins. EMBO J 5:823–826PubMedGoogle Scholar
  20. Crippen GM (1977) A novel approach to calculation of conformation: distance geometry. J Comp Physiol 24:96–107Google Scholar
  21. Deisenhofer J (1981). Crystallographic refinement and atomic models of a human Fc fragment and its complex with fragment B of protein A fromStaphylococcus aureus at 2.9- and 2.8-Å resolution. Biochemistry 20:2361–2370PubMedGoogle Scholar
  22. Dickerson RE (1971) The structure of cytochromec and the rates of molecular evolution. J Mol Evol 1:26–45CrossRefPubMedGoogle Scholar
  23. Dickerson RE, Timkovitch R, almassy RJ (1976) The cytochrome fold and the evolution of bacterial energy metabolism. J Mol Biol 100:473–491PubMedGoogle Scholar
  24. Doolittle RF (1979) Protein evolution. In: Neurath H, Hill RL (eds) The proteins, vol IV, ed 3. Academic Press, New York, pp 1–118Google Scholar
  25. Doolittle RF (1981) Similar amino acid sequences: chance or common ancestry?. Science 214:149–159PubMedGoogle Scholar
  26. Eklund H, Nordström B, Zeppezauer E, Söderlund G, Ohlsson I, Boiwe T, Söderberg B-O, Tapia O, Brändén C-I, Ekeson E (1976) Three-dimensional structure of horse liver alcohol dehydrogenase at 2.4 Å resolution. J Mol Biol 102:27–59PubMedGoogle Scholar
  27. Epp O, Lattman EE, Schiffer M, Huber R, Palm W (1975) The molecular structure of a dimer composed of the Bence-Jones protein Rei refined at 2.0 Å resolution. Biochemistry 14:4943–4952CrossRefPubMedGoogle Scholar
  28. Eventoff W, Rossmann MG (1975) The evolution of dehydrogenases and kinases. CRC Crit Rev Biochem 3:111–140PubMedGoogle Scholar
  29. Felsenstein J (1985) Confidence limits on phylogenies: an approach using the bootstrap. Evolution 39:783–791Google Scholar
  30. Feng D-F, Doolittle RF (1987) Progressive sequence alignment as a prerequisite to correct phylogenetic trees. J Mol Evol 25: 351–360PubMedGoogle Scholar
  31. Feng D-F, Johnson MS, Doolittle RF (1985) Aligning amino acid sequences: comparison of commonly used methods. J Mol Evol 21:112–125CrossRefGoogle Scholar
  32. Fermi G, Perutz M, Shaanan B, Fourme R (1984) The crystal structure of human deoxyhaemoglobin at 1.74 Å resolution. J Mol Biol 175:159–174CrossRefPubMedGoogle Scholar
  33. Ferro DR, Hermans J (1977) A different best rigid-body molecular fit routine. Acta Crystallogr A33:345–347CrossRefGoogle Scholar
  34. Fitch WM, Margoliash E (1967) Construction of phylogenetic trees. Science 15:279–284Google Scholar
  35. Fredman ML (1984) Computing evolutionary similarity measures with length independent gap penalties. Bull Math Biol 46:553–566CrossRefGoogle Scholar
  36. Frier JA, Perutz MF (1977) Structure of human foetal deoxyhaemoglobin. J Mol Biol 112:97–112PubMedGoogle Scholar
  37. Fujinaga M, James MNG (1987) Rat submaxillary gland protease, tonin. Structure solution and refinement at 1.8 Å resolution. J Mol Biol 195:373–396CrossRefPubMedGoogle Scholar
  38. Fujinaga M, Delbaere LTJ, Brayer GD, James MNG (1985) Refined structure ofα-lytic proteinase at 1.7 Å resolution. Analysis of hydrogen bonding and solvent structure. J Mol Biol 184:479–502CrossRefPubMedGoogle Scholar
  39. Furey W, Wang BC, Yoo CS, Sax M (1983) Structure of a novel Bence-Jones protein (Rhe) fragment at 1.6 Å resolution. J Mol Biol 167:661–692PubMedGoogle Scholar
  40. Girling RL, Houston TE, Schmidt WC, Amma EL (1980) Macromolecular structure refinement by restrained least-squares and interactive graphics as applied to sickling deer type III hemoglobin. Acta Crystallogr A36:43–50CrossRefGoogle Scholar
  41. Goodman M, Moore GW, Masuda G (1975) Darwinian evolution in the genealogy of haemoglobin. Nature 253:603–608CrossRefPubMedGoogle Scholar
  42. Haser R, Pierrot M, Frey M, Payan F, Astier JP, Bruschi M, Le Gall J (1979) Structure and sequence of the multihaem cytochromec 3. Nature 282:806–810CrossRefPubMedGoogle Scholar
  43. Higuchi Y, Kusunoki M, Matsuura Y, Yasuoka N, Kakudo M (1984) Refined structure of cytochromec 3 at 1.8 Å resolution. J Mol Biol 172:109–139CrossRefPubMedGoogle Scholar
  44. Honzatko RB, Hendrickson WA, Love WE (1985) Refinement of a molecular model for lamprey hemoglobin fromPetromyzon marinus J Mol Biol 184:147–164CrossRefPubMedGoogle Scholar
  45. Hotelling H (1933) Analysis of a complex of statistical variables into principal components. J Educ Psychol 24:417–441Google Scholar
  46. Hubbard TJP, Blundell TL (1987) Comparison of solvent-inaccessible cores of homologous proteins: definitions useful for protein modelling. Protein Eng 1:159–171PubMedGoogle Scholar
  47. Hunt LT, Hurst-Calderone S, Dayhoff MO (1978) Globins. In: Dayhoff MO (ed) Atlas of protein sequence and structure, vol 5, suppl 3. National Biomedical Research Foundation. Washington DC, pp 229–249Google Scholar
  48. James MNG, Sielecki AR, Brayer GD, Delbaere LTJ, Bauer C-A (1980) Structures of product and inihibitor complexes ofStreptomyces griseus protease A at 1.8 Å resolution. A model for serine proteinase catalysis. J Mol Biol 144:43–88CrossRefPubMedGoogle Scholar
  49. Jennings A (1978) Matrix computations for engineers and scientists. John Wiley and Sons, ChichesterGoogle Scholar
  50. Kabsch W (1978) A discussion of the solution for the best rotation to relate two sets of vectors. Acta Crystallogr A34: 827–828CrossRefGoogle Scholar
  51. Kenknight CE (1984) Comparison of methods of matching protein structures. Acta Crystallogr A40:708–712CrossRefGoogle Scholar
  52. Kernighan BW, Ritchie DM (1978) The C programming language. Prentice-Hall, Englewoods Cliffs NJGoogle Scholar
  53. Kortt AA, Burns JE, Trinick MJ, Appleby CA (1985) The amino acid sequence of hemoglobin I fromParasponia andersonii, a nonleguminous plant. FEBS Lett 180:55–60CrossRefGoogle Scholar
  54. Lazure C, Leduc C, Seidah NG, Thilbault G, Genest J, Chritien M (1984) Amino acid similarity of rat submaxillary tonin reveals similarities to serine proteases. Nature 307:555–558CrossRefPubMedGoogle Scholar
  55. Lesk AM, Chothia C (1980) How different amino acid sequences determine similar protein structures: the structure and evolutionary dynamics of the globins. J Mol Biol 136: 225–270CrossRefPubMedGoogle Scholar
  56. Lesk AM, Chothia C (1982) Evolution of proteins formed by β-sheets. II. The core of the immunoglobulin domains. J Mol Biol 160:325–342CrossRefPubMedGoogle Scholar
  57. Leunissen JAM, de Jong WW (1986) Phylogenetic trees constructured from the hydrophobic values of protein sequences. J Theor Biol 119:189–196PubMedGoogle Scholar
  58. Marquart M, Deisenhofer J, Huber R, Palm W (1980) Crystallographic refinement and atomic models of the intact immunoglobulin molecule Kol and its antigen-binding fragment at 3.0 Å and 1.9 Å resolution. J Mol Biol 141:369–391CrossRefPubMedGoogle Scholar
  59. Matsuura Y, Takano T, Kickerson RE (1982) Structure of cytochromec 551 fromP. aeruginosa refined at 1.6 Å resolution and comparison of the two redox forms. J Mol Biol 156:389–409CrossRefPubMedGoogle Scholar
  60. Matthews BW, Rossmann MG (1985) Comparison of protein structures. Methods Enzymol 115:397–420PubMedGoogle Scholar
  61. McLachlan AD (1979) Gene duplications in the structural evolution of chymotrypsin. J Mol Biol 128:49–79CrossRefPubMedGoogle Scholar
  62. McLachlan AD (1982) Rapid comparison of protein structures, Acta Crystallogr A34:871–873CrossRefGoogle Scholar
  63. Meyer E, Cole G, Radahakrishnan R, Epp O (1988) Structure of native porcine pancreatic elastase at 1.65 Å resolution. Acta Crystallogr B44:26–38CrossRefPubMedGoogle Scholar
  64. Moras D, Olsen KW, Sabesan MN, Buehner M, Ford GC, Rossmann MG (1975) Studies of the asymmetry in the three dimensional structure of lobster D-glyceraldehyde-3-phosphate dehydrogenase. J Biol Chem 250:9137–9162PubMedGoogle Scholar
  65. Needleman SA, Wunsch CD (1970) A general method applicable to the search for similarities in the amino acid sequence of two proteins. J Mol Biol 48:443–453CrossRefPubMedGoogle Scholar
  66. Ochi H, Hata Y, Tanaka N, Kanudo M, Sakurai T, Aihara S, Morita Y (1983) Structure of rice ferricytochromec at 2.0 Å resolution. J Mol Biol 166:407–418PubMedGoogle Scholar
  67. Ohlsson I, Nordström B, Brändén C-I (1974) Structural and functional similarities within the coenzyme binding domains of dehydrogenases. J Mol Biol 89:339–354CrossRefPubMedGoogle Scholar
  68. Padlan EA, Love WE (1985) Refined crystal structure of deoxyhemoglobin S. I. Restrained least-squares refinement at 3.0-Å resolution. J Biol Chem 260:8272–8279PubMedGoogle Scholar
  69. Pai EF, Karplus PA, Schulz GE (1988) Crystallographic analysis of the binding of NADPH, NADPH fragments, and NADPH analogues to glutathione reductase. Biochemistry 27:4465–4474CrossRefPubMedGoogle Scholar
  70. Pierrot M, Haser R, Frey M, Payan F, Astier J-P (1982) Crystal structures and electron transfer properties of cytochromec 3. J Biol Chem 257:14341–14348PubMedGoogle Scholar
  71. Rao ST, Rossmann MG (1973) Comparison of super-secondary structures in proteins. J Mol Biol 76:241–256CrossRefPubMedGoogle Scholar
  72. Read RJ, James MNG (1988) Refined crystal structure ofStreptomyces griseus trypsin at 1.7 Å resolution. J Mol Biol 200: 523–551CrossRefPubMedGoogle Scholar
  73. Reynolds RA, Remington SJ, Weaver LH, Fisher RG, Anderson WF, Ammon HL, Matthews BW (1985) Structure of a serine protease from rat mast cells determined from twinned crystals by isomorphous and molecular replacement. Acta Crystallogr B41:139–147CrossRefGoogle Scholar
  74. Richardson JS (1977) β-sheet topology and the relatedness of proteins. Nature 268:495–500CrossRefPubMedGoogle Scholar
  75. Rossmann MG, Moras D, Olsen KW (1974) Chemical and biological evolution of a nucleotide-binding protein. Nature 250:194–199CrossRefPubMedGoogle Scholar
  76. Salemme FR, Freer ST, Xuong NH, Alden RA, Kraut J (1973) The structure of oxidized cytochromec 2 ofRhodospirillum rubrum. J Biol Chem 248:3910–3921PubMedGoogle Scholar
  77. Šali A, Turk V (1987) Prediction of the secondary structures of stefins and cystatins, the low-molecular mass protein inhibitors of cysteine proteinases. Biol Chem Hoppe-Seyler 368: 493–499PubMedGoogle Scholar
  78. Saul FA, Amzel LM, Poljack RJ (1978) Preliminary refinement and structural analysis of the FAB fragment from human immunoglobulin NEW at 2.0 Å resolution. J Biol Chem 253: 585–597PubMedGoogle Scholar
  79. Schreuder HA, van der Laan JM, Hol WGT, Drenth J (1988) Crystal structure ofp-hydroxybenzoate hydroxylase complexed with its reaction product. J Mol Biol 199:637–648CrossRefPubMedGoogle Scholar
  80. Schulz GE, Schirmer RH, Sachsenheimer W, Pai EF (1978) The structure of the flavoenzyme glutathione reductase. Nature 273:120–124CrossRefPubMedGoogle Scholar
  81. Schwartz RM, Dayhoff MO (1978) Cytochromes. In: Dayhoff MO (ed) Atlas of protein sequence and structure, vol 5, suppl 3. National Biomedical Research Foundation. Washington DC, pp 29–44Google Scholar
  82. Shaanan B (1983) Structure of human oxyhaemoglobin at 2.1 Å resolution. J Mol Biol 171:31–59PubMedGoogle Scholar
  83. Steigemann W, Weber E (1979) Structure of erythrocruorin in different ligand states refined at 1.4 Å resolution. J Mol Biol 127:309–338CrossRefPubMedGoogle Scholar
  84. Sutcliffe MJ, Haneef I, Carney D, Blundell TL (1987a) Knowledge based modelling of homologous proteins, part I: threedimensional frameworks derived from simultaneous superposition of multiple structures. Protein Eng 1:377–384PubMedGoogle Scholar
  85. Sutcliffe MJ, Hayes FRF, Blundell TL (1987b) Knowledgebased modelling of homologous proteins, part II: rules for the conformations of substituted sidechains. Protein Eng 1:385–392PubMedGoogle Scholar
  86. Takano T (1977) Structure of myoglobin at 2.0 Å resolution, II. Structure of deoxymyoglobin from sperm whale. J Mol Biol 110:569–584PubMedGoogle Scholar
  87. Takano T, Dickerson RE (1981a) Conformational changes of cytochromec. I. Ferrocytochromec structure refined at 1.5 Å resolution. J Mol Biol 153:79–94CrossRefPubMedGoogle Scholar
  88. Takano T, Dickerson RE (1981b) Conformational changes of cytochromec. II. Ferricytochromec refinement at 1.8 Å resolution and comparison with the ferrocytochrome structure. J Mol Biol 153:95–115CrossRefPubMedGoogle Scholar
  89. Thieme R, Pai EF, Schirmer RH, Schulz GE (1981) Threedimensional structure of glutathione reductase at 2 Å resolution. J Mol Biol 152:763–782CrossRefPubMedGoogle Scholar
  90. Thorndike RM (1978) Correlation procedures for research. Gardner Press, New York, pp 1–340Google Scholar
  91. Timkovich R, Dickerson RE (1976) The structure ofParacoccus denitrificans cytochromec 550. J Biol Chem 251:4033–4046PubMedGoogle Scholar
  92. Tsukada H, Blow DM (1985) Structure ofα-chymotrypsin refined at 1.68 Å resolution. J Mol Biol 184:703–711CrossRefPubMedGoogle Scholar
  93. Wakabayashi S, Matsubara H, Webster DA (1986) Primary sequence of a dimeric bacterial hemoglobin fromVitreoscilla. Nature 322:481–483CrossRefPubMedGoogle Scholar
  94. Walter J, Steigemann W, Singh JP, Bartunik H, Bode W, Huber R (1982) On the disordered activation domain in trypsinogen. Chemical labelling and low-temperature crystallography. Acta Crystallogr B38:1462–1472CrossRefGoogle Scholar
  95. White, JL, Hackert ML, Buehner M, Adams MJ, Ford GC, Lentz PJ, Smiley IE, Steindel SJ, Rossmann MG (1976) A comparison of the structures of apo dogfish M4 lactate dehydrogenase and its ternary complexes. J Mol Biol 102:759–779CrossRefPubMedGoogle Scholar
  96. White HE, Driessen HPC, Slingsby C, Moss DS, Turnell WG, Lindley PF, (1988a) The use of pseudosymmetry in the rotation function of γIVa-crystallin. Acta Crystallogr B44:172–178CrossRefPubMedGoogle Scholar
  97. White HE, Driessen HPC, Slingsby C, Moss DS, Lindley PF (1988b) Packing interactions in the eye-lens: structural analysis, internal symmetry and lattice interactions of bovine gamma-IVa crystallin. J Mol Biol 207:217–235CrossRefGoogle Scholar
  98. Wierenga RK, Drenth J, Schulz GE (1983) Comparison of the three-dimensional protein and nucleotide structure of the FAD-binding domain ofp-hydroxybenzoate hydroxylase with the FAD- as well as NADPH-binding domains of glutathione reductase. J Mol Biol 167:725–739PubMedGoogle Scholar
  99. Wierenga RK, De Maeyer MCH, Hol WGJ (1985) Interactions of pyrophosphate moieties withα-helices in dinucleotide binding proteins. Biochemistry 24:1346–1357CrossRefGoogle Scholar
  100. Wierenga RK, Terpstra P, Hol WG (1986) Prediction of the occurrence of the ADP βαβ-fold in proteins, using amino acid fingerprints. J Mol Biol 187:101–107CrossRefPubMedGoogle Scholar
  101. Wistow G, Turnell B, Summers L, Slingsby C, Moss D, Miller L, Lindley P, Blundell T (1983) X-ray analysis of the eye lens protein gamma-II crystallin at 1.9 Å resolution. J Mol Biol 170:175–202PubMedGoogle Scholar
  102. Young CL, Barker WC, Tomaselli CM, Dayhoff MO (1978) Serine proteases. In: Dayhoff MO (ed) Atlas of protein sequence and structure, vol 5, suppl 3. National Biomedical Research Foundation, Washington DC, pp 73–93Google Scholar

Copyright information

© Springer-Verlag New York Inc 1990

Authors and Affiliations

  • Mark S. Johnson
    • 1
  • Michael J. Sutcliffe
    • 1
  • Tom L. Blundell
    • 1
  1. 1.Laboratory of Molecular Biology, Department of Crystallography, Birkbeck CollegeUniversity of LondonLondonUK

Personalised recommendations