A Specific A/T Polymorphism in Western Tyrosine Phosphorylation B-Motifs Regulates Helicobacter pylori CagA Epithelial Cell Interactions

PLoS Pathogens

Volumn 11, Issue 2, 2015, Pages

  Zhang, Xue Song ^a   Tegtmeyer, Nicole ^b   Traube, Leah ^a   Jindal, Shawn ^a   Perez Perez, Guillermo ^a   Sticht, Heinrich ^b   Backert, Steffen ^b   Blaser, Martin J ^a  

^a NEW YORK UNIVERSITY SCHOOL OF MEDICINE   (United States)

^b UNIVERSITY OF ERLANGEN NUREMBERG   (Germany)

Author keywords

[No Author keywords available]

Indexed keywords

CAGA PROTEIN; INTERLEUKIN 8; PHOSPHATIDYLINOSITOL 3 KINASE; POLYCLONAL ANTIBODY; PROTEIN KINASE B; BACTERIAL ANTIGEN; BACTERIAL PROTEIN; CAGA PROTEIN, HELICOBACTER PYLORI;

AMINO ACID SEQUENCE; ARTICLE; CANCER RISK; CELL ELONGATION; CELL INTERACTION; COCULTURE; COMPUTER MODEL; CONTROLLED STUDY; DUODENUM ULCER; ENZYME LINKED IMMUNOSORBENT ASSAY; EPITHELIUM CELL; EPIYA MOTIF; EPIYT MOTIF; ESIYA MOTIF; ESIYT MOTIF; ESOPHAGITIS; GASTRITIS; HELICOBACTER PYLORI; HOMOLOGOUS RECOMBINATION; HOST PATHOGEN INTERACTION; HUMAN; HUMAN CELL; HUMAN CELL CULTURE; HUMMINGBIRD PHENOTYPE; IMMUNOPRECIPITATION; NONHUMAN; PEPTIDE SYNTHESIS; PHENOTYPE; POLYMERASE CHAIN REACTION; PROTEIN ANALYSIS; PROTEIN INTERACTION; PROTEIN MOTIF; PROTEIN PHOSPHORYLATION; SHUTTLE VECTOR; SINGLE NUCLEOTIDE POLYMORPHISM; SITE DIRECTED MUTAGENESIS; STOMACH CANCER; THREE DIMENSIONAL IMAGING; TYPE IV SECRETION SYSTEM; WESTERN BLOTTING; CELL LINE; GENETICS; IMMUNOBLOTTING; MICROBIOLOGY; PHOSPHORYLATION;

HELICOBACTER PYLORI;

AMINO ACID MOTIFS; ANTIGENS, BACTERIAL; BACTERIAL PROTEINS; CELL LINE; COCULTURE TECHNIQUES; EPITHELIAL CELLS; HELICOBACTER PYLORI; HOST-PATHOGEN INTERACTIONS; HUMANS; IMMUNOBLOTTING; IMMUNOPRECIPITATION; PHOSPHORYLATION; POLYMORPHISM, SINGLE NUCLEOTIDE;

EID: 84924359581     PISSN: 15537366     EISSN: 15537374     Source Type: Journal    
DOI: 10.1371/journal.ppat.1004621     Document Type: Article

References (87)

1. Murata-Kamiya N, (2011) Pathophysiological functions of the CagA oncoprotein during infection by Helicobacter pylori. Microbes Infect 13: 799–807. doi: 10.1016/j.micinf.2011.03.011 21477660
2. Marshall BJ, Warren JR, (1984) Unidentified curved bacilli in the stomach of patients with gastritis and peptic ulceration. Lancet 1: 1311–1315. 6145023
3. Linz B, Balloux F, Moodley Y, Manica A, Liu H, et al. (2007) An African origin for the intimate association between humans and Helicobacter pylori. Nature 445: 915–918. doi: 10.1038/nature05562 17287725
4. Achtman M, Azuma T, Berg DE, Ito Y, Morelli G, et al. (1999) Recombination and clonal groupings within Helicobacter pylori from different geographical regions. Mol Microbiol 32: 459–470. 10320570
5. Wroblewski LE, Peek RM, Jr.Wilson KT, (2010) Helicobacter pylori and gastric cancer: factors that modulate disease risk. Clin Microbiol Rev 23: 713–739. doi: 10.1128/CMR.00011-10 20930071
6. Parsonnet J, Hansen S, Rodriguez L, Gelb AB, Warnke RA, et al. (1994) Helicobacter pylori infection and gastric lymphoma. N Engl J Med 330: 1267–1271. 8145781
7. el-Serag HB, Sonnenberg A, (1998) Opposing time trends of peptic ulcer and reflux disease. Gut 43: 327–333. 9863476
8. Wiseman EF, Ang YS, (2011) Risk factors for neoplastic progression in Barrett’s esophagus. World J Gastroenterol 17: 3672–3683. doi: 10.3748/wjg.v17.i32.3672 21990948
9. Eucker TP, Samuelson DR, Hunzicker-Dunn M, Konkel ME (2014) The focal complex of epithelial cells provides a signaling platform for interleukin-8 induction in response to bacterial pathogens. Cell Microbiol.
10. Oertli M, Muller A, (2012) Helicobacter pylori targets dendritic cells to induce immune tolerance, promote persistence and confer protection against allergic asthma. Gut Microbes 3: 566–571. doi: 10.4161/gmic.21750 22895083
11. Blaser MJ, Perez-Perez GI, Kleanthous H, Cover TL, Peek RM, et al. (1995) Infection with Helicobacter pylori strains possessing cagA is associated with an increased risk of developing adenocarcinoma of the stomach. Cancer Res 55: 2111–2115. 7743510
12. Hatakeyama M, (2014) Helicobacter pylori CagA and Gastric Cancer: A Paradigm for Hit-and-Run Carcinogenesis. Cell Host Microbe 15: 306–316. doi: 10.1016/j.chom.2014.02.008 24629337
13. Jurik A, Hausser E, Kutter S, Pattis I, Prassl S, et al. (2010) The coupling protein Cag{beta} and its interaction partner CagZ are required for type IV secretion of the Helicobacter pylori CagA protein. Infect Immun.
14. Tummuru MK, Cover TL, Blaser MJ, (1993) Cloning and expression of a high-molecular-mass major antigen of Helicobacter pylori: evidence of linkage to cytotoxin production. Infect Immun 61: 1799–1809. 8478069
15. Tegtmeyer N, Wessler S, Backert S (2011) Role of the cag-pathogenicity island encoded type IV secretion system in Helicobacter pylori pathogenesis. Febs J.
16. Yamaoka Y, El-Zimaity HM, Gutierrez O, Figura N, Kim JG, et al. (1999) Relationship between the cagA 3’ repeat region of Helicobacter pylori, gastric histology, and susceptibility to low pH. Gastroenterology 117: 342–349. 10419915
17. Azuma T, Yamakawa A, Yamazaki S, Fukuta K, Ohtani M, et al. (2002) Correlation between variation of the 3’ region of the cagA gene in Helicobacter pylori and disease outcome in Japan. J Infect Dis 186: 1621–1630. 12447739
18. Furuta Y, Yahara K, Hatakeyama M, Kobayashi I, (2011) Evolution of cagA Oncogene of Helicobacter pylori through Recombination. PLoS One 6: e23499. doi: 10.1371/journal.pone.0023499 21853141
19. Higashi H, Yokoyama K, Fujii Y, Ren S, Yuasa H, et al. (2005) EPIYA motif is a membrane-targeting signal of Helicobacter pylori virulence factor CagA in mammalian cells. J Biol Chem 280: 23130–23137. 15831497
20. Nagase L, Murata-Kamiya N, Hatakeyama M (2011) Potentiation of Helicobacter pylori CagA virulence through homodimerization. J Biol Chem.
21. Backert S, Feller SM, Wessler S, (2008) Emerging roles of Abl family tyrosine kinases in microbial pathogenesis. Trends Biochem Sci 33: 80–90. doi: 10.1016/j.tibs.2007.10.006 18182299
22. Stein M, Bagnoli F, Halenbeck R, Rappuoli R, Fantl WJ, et al. (2002) c-Src/Lyn kinases activate Helicobacter pylori CagA through tyrosine phosphorylation of the EPIYA motifs. Mol Microbiol 43: 971–980. 11929545
23. Tammer I, Brandt S, Hartig R, Konig W, Backert S, (2007) Activation of Abl by Helicobacter pylori: a novel kinase for CagA and crucial mediator of host cell scattering. Gastroenterology 132: 1309–1319. 17408661
24. Suzuki M, Mimuro H, Kiga K, Fukumatsu M, Ishijima N, et al. (2009) Helicobacter pylori CagA phosphorylation-independent function in epithelial proliferation and inflammation. Cell Host Microbe 5: 23–34. doi: 10.1016/j.chom.2008.11.010 19154985
25. Muller A, (2012) Multistep activation of the Helicobacter pylori effector CagA. J Clin Invest 122: 1192–1195. doi: 10.1172/JCI61578 22378039
26. Backert S, Tegtmeyer N, Selbach M, (2010) The Versatility of Helicobacter pylori CagA Effector Protein Functions: The Master Key Hypothesis. Helicobacter 15: 163–176. doi: 10.1111/j.1523-5378.2010.00759.x 20557357
27. Hayashi T, Senda M, Morohashi H, Higashi H, Horio M, et al. (2012) Tertiary structure-function analysis reveals the pathogenic signaling potentiation mechanism of Helicobacter pylori oncogenic effector CagA. Cell Host Microbe 12: 20–33. doi: 10.1016/j.chom.2012.05.010 22817985
28. Selbach M, Paul FE, Brandt S, Guye P, Daumke O, et al. (2009) Host cell interactome of tyrosine-phosphorylated bacterial proteins. Cell Host Microbe 5: 397–403. doi: 10.1016/j.chom.2009.03.004 19380118
29. Ne Sbreve Ic D, Miller MC, Quinkert ZT, Stein M, Chait BT, et al. (2009) Helicobacter pylori CagA inhibits PAR1-MARK family kinases by mimicking host substrates. Nat Struct Mol Biol.
30. Nesic D, Buti L, Lu X, Stebbins CE, (2014) Structure of the Helicobacter pylori CagA oncoprotein bound to the human tumor suppressor ASPP2. Proc Natl Acad Sci U S A 111: 1562–1567. doi: 10.1073/pnas.1320631111 24474782
31. Lee IO, Kim JH, Choi YJ, Pillinger MH, Kim SY, et al. (2010) Helicobacter pylori CagA phosphorylation status determines the gp130-activated SHP2/ERK and JAK/STAT signal transduction pathways in gastric epithelial cells. J Biol Chem 285: 16042–16050. doi: 10.1074/jbc.M110.111054 20348091
32. Neel BG, Gu H, Pao L, (2003) The ‘Shp’ing news: SH2 domain-containing tyrosine phosphatases in cell signaling. Trends Biochem Sci 28: 284–293. 12826400
33. Saadat I, Higashi H, Obuse C, Umeda M, Murata-Kamiya N, et al. (2007) Helicobacter pylori CagA targets PAR1/MARK kinase to disrupt epithelial cell polarity. Nature 447: 330–333. 17507984
34. Higashi H, Tsutsumi R, Muto S, Sugiyama T, Azuma T, et al. (2002) SHP-2 tyrosine phosphatase as an intracellular target of Helicobacter pylori CagA protein. Science 295: 683–686. 11743164
35. Segal ED, Cha J, Lo J, Falkow S, Tompkins LS, (1999) Altered states: involvement of phosphorylated CagA in the induction of host cellular growth changes by Helicobacter pylori. Proc Natl Acad Sci U S A 96: 14559–14564. 10588744
36. Higashi H, Nakaya A, Tsutsumi R, Yokoyama K, Fujii Y, et al. (2004) Helicobacter pylori CagA induces Ras-independent morphogenetic response through SHP-2 recruitment and activation. J Biol Chem 279: 17205–17216. 14963045
37. Nagy TA, Frey MR, Yan F, Israel DA, Polk DB, et al. (2009) Helicobacter pylori regulates cellular migration and apoptosis by activation of phosphatidylinositol 3-kinase signaling. J Infect Dis 199: 641–651. doi: 10.1086/596660 19199544
38. Ohnishi N, Yuasa H, Tanaka S, Sawa H, Miura M, et al. (2008) Transgenic expression of Helicobacter pylori CagA induces gastrointestinal and hematopoietic neoplasms in mouse. Proc Natl Acad Sci U S A 105: 1003–1008. doi: 10.1073/pnas.0711183105 18192401
39. Ren S, Higashi H, Lu H, Azuma T, Hatakeyama M, (2006) Structural basis and functional consequence of Helicobacter pylori CagA multimerization in cells. J Biol Chem 281: 32344–32352. 16954210
40. Suzuki R, Shiota S, Yamaoka Y, (2013) Molecular epidemiology, population genetics, and pathogenic role of Helicobacter pylori. Infect Genet Evol 12: 203–213. doi: 10.1016/j.meegid.2011.12.002 22197766
41. Logan RP, Berg DE, (1996) Genetic diversity of Helicobacter pylori. Lancet 348: 1462–1463. 8942769
42. Alm RA, Trust TJ, (1999) Analysis of the genetic diversity of Helicobacter pylori: the tale of two genomes. J Mol Med 77: 834–846. 10682319
43. Falush D, Wirth T, Linz B, Pritchard JK, Stephens M, et al. (2003) Traces of human migrations in Helicobacter pylori populations. Science 299: 1582–1585. 12624269
44. Aras RA, Lee Y, Kim SK, Israel D, Peek RM, Jr.et al. (2003) Natural variation in populations of persistently colonizing bacteria affect human host cell phenotype. J Infect Dis 188: 486–496. 12898434
45. Azuma T, Yamazaki S, Yamakawa A, Ohtani M, Muramatsu A, et al. (2004) Association between diversity in the Src homology 2 domain—containing tyrosine phosphatase binding site of Helicobacter pylori CagA protein and gastric atrophy and cancer. J Infect Dis 189: 820–827. 14976598
46. Hatakeyama M, (2004) Oncogenic mechanisms of the Helicobacter pylori CagA protein. Nat Rev Cancer 4: 688–694. 15343275
47. Higashi H, Tsutsumi R, Fujita A, Yamazaki S, Asaka M, et al. (2002) Biological activity of the Helicobacter pylori virulence factor CagA is determined by variation in the tyrosine phosphorylation sites. Proc Natl Acad Sci U S A 99: 14428–14433. doi: 10.1073/pnas.222375399 12391297
48. Jones KR, Joo YM, Jang S, Yoo YJ, Lee HS, et al. (2009) Polymorphism in the CagA EPIYA Motif Impacts Development of Gastric Cancer. J Clin Microbiol.
49. Kim SY, Lee YC, Kim HK, Blaser MJ, (2006) Helicobacter pylori CagA transfection of gastric epithelial cells induces interleukin-8. Cell Microbiol 8: 97–106. 16367869
50. Huang H, Li L, Wu C, Schibli D, Colwill K, et al. (2008) Defining the specificity space of the human SRC homology 2 domain. Mol Cell Proteomics 7: 768–784. 17956856
51. Suzuki M, Mimuro H, Suzuki T, Park M, Yamamoto T, et al. (2005) Interaction of CagA with Crk plays an important role in Helicobacter pylori-induced loss of gastric epithelial cell adhesion. J Exp Med 202: 1235–1247. doi: 10.1084/jem.20051027 16275761
52. Crabtree JE, Wyatt JI, Trejdosiewicz LK, Peichl P, Nichols PH, et al. (1994) Interleukin-8 expression in Helicobacter pylori infected, normal, and neoplastic gastroduodenal mucosa. J Clin Pathol 47: 61–66. 8132812
53. Beswick EJ, Reyes VE, (2008) Macrophage migration inhibitory factor and interleukin-8 produced by gastric epithelial cells during Helicobacter pylori exposure induce expression and activation of the epidermal growth factor receptor. Infect Immun 76: 3233–3240. doi: 10.1128/IAI.01534-07 18474653
54. Argent RH, Hale JL, El-Omar EM, Atherton JC, (2008) Differences in Helicobacter pylori CagA tyrosine phosphorylation motif patterns between western and East Asian strains, and influences on interleukin-8 secretion. J Med Microbiol 57: 1062–1067. doi: 10.1099/jmm.0.2008/001818-0 18719174
55. Takata S, Ito M, Wada Y, Yoshihara M, Tanaka S, et al. (2009) Pathogenetic role of the tyrosine-phosphorylated CagA EPIYA sequence of Helicobacter pylori in histological gastritis in Japanese patients. J Gastroenterol.
56. Matsunari O, Shiota S, Suzuki R, Watada M, Kinjo N, et al. (2012) Association between Helicobacter pylori virulence factors and gastroduodenal diseases in Okinawa, Japan. J Clin Microbiol 50: 876–883. doi: 10.1128/JCM.05562-11 22189111
57. Lind J, Backert S, Pfleiderer K, Berg DE, Yamaoka Y, et al. (2014) Systematic analysis of phosphotyrosine antibodies recognizing single phosphorylated EPIYA-motifs in CagA of Western-type Helicobacter pylori strains. PLoS One 9: e96488. doi: 10.1371/journal.pone.0096488 24800748
58. Ubersax JA, Ferrell JE, Jr. (2007) Mechanisms of specificity in protein phosphorylation. Nat Rev Mol Cell Biol 8: 530–541. 17585314
59. Li SP, Chen XJ, Sun AH, Zhao JF, Yan J, (2010) CagA(+)H.pylori Induces Akt1 Phosphorylation and Inhibits Transcription of p21(WAF1/CIP1) and p27(KIP1) via PI3K/Akt1 Pathway. Biomed Environ Sci 23: 273–278. doi: 10.1016/S0895-3988(10)60063-3 20934114
60. Huang F-C, Li Q, Cherayil BJ, (2005) A phosphatidyl-inositol-3-kinase-dependent anti-inflammatory pathway activated by Salmonella in epithelial cells. FEMS Microbiology Letters 243: 265–270. 15668028
61. Schneider N, Krishna U, Romero-Gallo J, Israel DA, Piazuelo MB, et al. (2009) Role of Helicobacter pylori CagA Molecular Variations in Induction of Host Phenotypes with Carcinogenic Potential. J Infect Dis 199: 1218–1221. doi: 10.1086/597416 19278338
62. Zhang Y, Takeuchi H, Nishioka M, Morimoto N, Kamioka M, et al. (2009) Relationship of IL-8 production and the CagA status in AGS cells infected with Helicobacter pylori exposed to low pH and activating transcription factor 3 (ATF3). Microbiol Res 164: 180–190. 17449233
63. Kodaman N, Pazos A, Schneider BG, Piazuelo MB, Mera R, et al. (2014) Human and Helicobacter pylori coevolution shapes the risk of gastric disease. Proc Natl Acad Sci U S A 111: 1455–1460. doi: 10.1073/pnas.1318093111 24474772
64. Ando T, Peek RM, Jr.Lee YC, Krishna U, Kusugami K, et al. (2002) Host cell responses to genotypically similar Helicobacter pylori isolates from United States and Japan. Clin Diagn Lab Immunol 9: 167–175. doi: 10.1128/CDLI.9.1.167-175.2002 11777849
65. Brandt S, Kwok T, Hartig R, Konig W, Backert S, (2005) NF-kappaB activation and potentiation of proinflammatory responses by the Helicobacter pylori CagA protein. Proc Natl Acad Sci U S A 102: 9300–9305. doi: 10.1073/pnas.0409873102 15972330
66. Zhu Y, Zhong X, Zheng S, Du Q, Xu W, (2005) Transformed immortalized gastric epithelial cells by virulence factor CagA of Helicobacter pylori through Erk mitogen-activated protein kinase pathway. Oncogene 24: 3886–3895. 15856031
67. Fruman DA, Rommel C, (2014) PI3K and cancer: lessons, challenges and opportunities. Nat Rev Drug Discov 13: 140–156. doi: 10.1038/nrd4204 24481312
68. Yuan TL, Cantley LC, (2008) PI3K pathway alterations in cancer: variations on a theme. Oncogene 27: 5497–5510. doi: 10.1038/onc.2008.245 18794884
69. Tsutsumi R, Takahashi A, Azuma T, Higashi H, Hatakeyama M, (2006) Focal adhesion kinase is a substrate and downstream effector of SHP-2 complexed with Helicobacter pylori CagA. Mol Cell Biol 26: 261–276. doi: 10.1128/MCB.26.1.261-276.2006 16354697
70. Vlahos CJ, Matter WF, Hui KY, Brown RF, (1994) A specific inhibitor of phosphatidylinositol 3-kinase, 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (LY294002). J Biol Chem 269: 5241–5248. 8106507
71. Tsutsumi R, Higashi H, Higuchi M, Okada M, Hatakeyama M, (2003) Attenuation of Helicobacter pylori CagA × SHP-2 signaling by interaction between CagA and C-terminal Src kinase. J Biol Chem 278: 3664–3670. 12446738
72. Tomb JF, White O, Kerlavage AR, Clayton RA, Sutton GG, et al. (1997) The complete genome sequence of the gastric pathogen Helicobacter pylori. Nature 388: 539–547. 9252185
73. Mueller D, Tegtmeyer N, Brandt S, Yamaoka Y, De Poire E, et al. (2012) c-Src and c-Abl kinases control hierarchic phosphorylation and function of the CagA effector protein in Western and East Asian Helicobacter pylori strains. J Clin Invest 122: 1553–1566. doi: 10.1172/JCI61143 22378042
74. Zhang XS, Blaser MJ, (2012) DprB facilitates inter- and intragenomic recombination in Helicobacter pylori. J Bacteriol 194: 3891–3903. doi: 10.1128/JB.00346-12 22609923
75. Tegtmeyer N, Rivas Traverso F, Rohde M, Oyarzabal OA, Lehn N, et al. (2013) Electron microscopic, genetic and protein expression analyses of Helicobacter acinonychis strains from a Bengal tiger. PLoS One 8: e71220. doi: 10.1371/journal.pone.0071220 23940723
76. Sambrook J, Fritsch EF, Maniatis T, (1989) Molecular Cloning, A Laboratory Manual. Cold Spring Harbor, NY: Cold Spring Harbor Laboratory Press.
77. Zhang XS, Blaser MJ, (2012) Natural transformation of an engineered Helicobacter pylori strain deficient in type II restriction endonucleases. J Bacteriol 194: 3407–3416. doi: 10.1128/JB.00113-12 22522893
78. Tegtmeyer N, Lind J, Schmid B, Backert S, (2014) Helicobacter pylori CagL Y58/E59 mutation turns-off type IV secretion-dependent delivery of CagA into host cells. PLoS One 9: e97782. doi: 10.1371/journal.pone.0097782 24893039
79. Tegtmeyer N, Wittelsberger R, Hartig R, Wessler S, Martinez-Quiles N, et al. (2011) Serine Phosphorylation of Cortactin Controls Focal Adhesion Kinase Activity and Cell Scattering Induced by Helicobacter pylori. Cell Host Microbe 9: 520–531. doi: 10.1016/j.chom.2011.05.007 21669400
80. Pillinger MH, Marjanovic N, Kim SY, Scher JU, Izmirly P, et al. (2005) Matrix metalloproteinase secretion by gastric epithelial cells is regulated by E prostaglandins and MAPKs. J Biol Chem 280: 9973–9979. 15640153
81. Bourzac KM, Botham CM, Guillemin K, (2007) Helicobacter pylori CagA induces AGS cell elongation through a cell retraction defect that is independent of Cdc42, Rac1, and Arp2/3. Infect Immun 75: 1203–1213. doi: 10.1128/IAI.01702-06 17194805
82. Tegtmeyer N, Hartig R, Delahay RM, Rohde M, Brandt S, et al. (2010) A small fibronectin-mimicking protein from bacteria induces cell spreading and focal adhesion formation. J Biol Chem.
83. Hirsch C, Tegtmeyer N, Rohde M, Rowland M, Oyarzabal OA, et al. (2012) Live Helicobacter pylori in the root canal of endodontic-infected deciduous teeth. J Gastroenterol 47: 936–940. doi: 10.1007/s00535-012-0618-8 22722905
84. Krause-Gruszczynska M, Boehm M, Rohde M, Tegtmeyer N, Takahashi S, et al. (2011) The signaling pathway of Campylobacter jejuni-induced Cdc42 activation: Role of fibronectin, integrin beta1, tyrosine kinases and guanine exchange factor Vav2. Cell Commun Signal 9: 32. doi: 10.1186/1478-811X-9-32 22204307
85. Nolte RT, Eck MJ, Schlessinger J, Shoelson SE, Harrison SC, (1996) Crystal structure of the PI 3-kinase p85 amino-terminal SH2 domain and its phosphopeptide complexes. Nat Struct Biol 3: 364–374. 8599763
86. Guex N, Peitsch MC, (1997) SWISS-MODEL and the Swiss-PdbViewer: an environment for comparative protein modeling. Electrophoresis 18: 2714–2723. 9504803
87. Sayle RA, Milner-White EJ, (1995) RASMOL: biomolecular graphics for all. Trends Biochem Sci 20: 374. 7482707