title: Characterization of parasite-specific indels and their proposed relevance for selective anthelminthic drug targeting.
abstract: Insertions and deletions (indels) are important sequence variants that are considered as phylogenetic markers that reflect evolutionary adaptations in different species. In an effort to systematically study indels specific to the phylum Nematoda and their structural impact on the proteins bearing them, we examined over 340,000 polypeptides from 21 nematode species spanning the phylum, compared them to non-nematodes and identified indels unique to nematode proteins in more than 3000 protein families. Examination of the amino acid composition revealed uneven usage of amino acids for insertions and deletions. The amino acid composition and cost, along with the secondary structure constitution of the indels, were analyzed in the context of their biological pathway associations. Species-specific indels could enable indel-based targeting for drug design in pathogens/parasites. Therefore, we screened the spatial locations of the indels in the parasite's protein 3D structures, determined the location of the indel and identified potential unique drug targeting sites. These indels could be confirmed by RNA-Seq data. Examples are presented illustrating the close proximity of some indels to established small-molecule binding pockets that can potentially facilitate selective targeting to the parasites and bypassing their host, thus reducing or eliminating the toxicity of the potential drugs. This study presents an approach for understanding the adaptation of pathogens/parasites at a molecular level, and outlines a strategy to identify such nematode-selective targets that remain essential to the organism. With further experimental characterization and validation, it opens a possible channel for the development of novel treatments with high target specificity, addressing both host toxicity and resistance concerns.
authors.affiliation: McDonnell Genome Institute, Washington University in St. Louis, St. Louis, MO, USA.
authors.forename: Qi
authors.initials: Q
authors.lastname: Wang
authors.affiliation: McDonnell Genome Institute, Washington University in St. Louis, St. Louis, MO, USA.
authors.forename: Esley
authors.initials: E
authors.lastname: Heizer
authors.affiliation: McDonnell Genome Institute, Washington University in St. Louis, St. Louis, MO, USA.
authors.forename: Bruce A
authors.initials: BA
authors.lastname: Rosa
authors.affiliation: Carbone Cancer Center, School of Medicine and Public Health, University of Wisconsin, Madison, WI, USA.
authors.forename: Scott A
authors.initials: SA
authors.lastname: Wildman
authors.affiliation: Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, 660 South Euclid Ave., St. Louis, MO, USA.
authors.forename: James W
authors.initials: JW
authors.lastname: Janetka
authors.affiliation: McDonnell Genome Institute, Washington University in St. Louis, St. Louis, MO, USA; Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO, USA; Department of Genetics, Washington University School of Medicine, St. Louis, MO, USA. Electronic address: mmitreva@genome.wustl.edu.
authors.forename: Makedonka
authors.initials: M
authors.lastname: Mitreva
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D019295:Computational Biology; D030541:Databases, Genetic; D055808:Drug Discovery; D006373:Helminthiasis / Q000188:drug therapy / Q000469:parasitology*; D006376:Helminths / Q000187:drug effects* / Q000235:genetics*; D006801:Humans; D054643:INDEL Mutation; D008958:Models, Molecular; D009348:Nematoda; D011487:Protein Conformation; D015800:Protozoan Proteins / Q000737:chemistry / Q000235:genetics
chemical_list: D015800:Protozoan Proteins
keywords: Adaptation; Drug targets; Insertions and deletions; Nematodes; Parasites; Selective targeting; Spatial structures of proteins
references.citation: Nucleic Acids Res. 2016 Jan 4;44(D1):D774-80
references.pmid: 26578572
references.citation: BMC Genomics. 2008;9:525
references.pmid: 18983679
references.citation: BMC Genomics. 2009;10:114
references.pmid: 19296854
references.citation: Mol Biol Evol. 1998 Jun;15(6):774-6
references.pmid: 9615459
references.citation: Nucleic Acids Res. 2000 Jan 1;28(1):27-30
references.pmid: 10592173
references.citation: Vet Parasitol. 2007 Aug 19;148(1):31-42
references.pmid: 17560034
references.citation: Nucleic Acids Res. 2012 Jan;40(Database issue):D512-8
references.pmid: 22127860
references.citation: Nat Genet. 2001 Jun;28(2):160-4
references.pmid: 11381264
references.citation: PLoS Negl Trop Dis. 2009;3(10):e538
references.pmid: 19855829
references.citation: Nucleic Acids Res. 2015 Jan;43(Database issue):D30-5
references.pmid: 25414350
references.citation: Proc Natl Acad Sci U S A. 2001 Jun 19;98(13):7360-5
references.pmid: 11416209
references.citation: Adv Parasitol. 1991;30:39-105
references.pmid: 2069074
references.citation: Nucleic Acids Res. 2014 Jan;42(Database issue):D789-93
references.pmid: 24194605
references.citation: J Med Chem. 2013 Mar 14;56(5):2087-96
references.pmid: 23409953
references.citation: Proteins. 2004 Jan 1;54(1):71-87
references.pmid: 14705025
references.citation: Trends Parasitol. 2004 Oct;20(10):469-76
references.pmid: 15363440
references.citation: BMC Plant Biol. 2006;6:12
references.pmid: 16784532
references.citation: Genome Res. 2003 Sep;13(9):2178-89
references.pmid: 12952885
references.citation: J Mol Biol. 1995 Oct 13;253(1):114-31
references.pmid: 7473707
references.citation: Bioinformatics. 2009 Dec 1;25(23):3185-6
references.pmid: 19789268
references.citation: J Biol Chem. 2012 Apr 6;287(15):11788-97
references.pmid: 22356915
references.citation: Int J Mol Sci. 2013;14(5):10438-64
references.pmid: 23698773
references.citation: Nat Genet. 2001 Dec;29(4):475-81
references.pmid: 11726933
references.citation: Biopolymers. 1983 Dec;22(12):2577-637
references.pmid: 6667333
references.citation: Curr Opin Genet Dev. 2000 Dec;10(6):602-5
references.pmid: 11088008
references.citation: J Comput Biol. 2009 Feb;16(2):159-67
references.pmid: 19193143
references.citation: BMC Bioinformatics. 2008;9:293
references.pmid: 18578882
references.citation: Nucleic Acids Res. 2015 Jan;43(Database issue):D698-706
references.pmid: 25392426
references.citation: ACS Chem Biol. 2013 Sep 20;8(9):1981-7
references.pmid: 23834437
references.citation: Nucleic Acids Res. 2011 Jan;39(Database issue):D411-9
references.pmid: 21071423
references.citation: Nat Rev Drug Discov. 2014 Mar;13(3):197-216
references.pmid: 24577401
references.citation: PLoS Negl Trop Dis. 2010;4(6):e701
references.pmid: 20544024
references.citation: J Comput Chem. 2005 Dec;26(16):1781-802
references.pmid: 16222654
references.citation: Curr Protoc Bioinformatics. 2011 Sep;Chapter 6:Unit 6.12.1-19
references.pmid: 21901743
references.citation: PLoS Negl Trop Dis. 2011 Dec;5(12):e1409
references.pmid: 22180794
references.citation: J Mol Biol. 1992 Mar 20;224(2):461-71
references.pmid: 1560462
references.citation: Nat Protoc. 2010 Apr;5(4):725-38
references.pmid: 20360767
references.citation: Genome Biol. 2013;14(4):R36
references.pmid: 23618408
references.citation: Mol Syst Biol. 2011;7:539
references.pmid: 21988835
references.citation: Genome Biol Evol. 2009 Jun 27;1:145-52
references.pmid: 20333185
references.citation: PLoS Genet. 2012 Jun;8(6):e1002803
references.pmid: 22761596
references.citation: Biochem J. 2013 Feb 1;449(3):581-94
references.pmid: 23301657
references.citation: BMC Bioinformatics. 2007;8:227
references.pmid: 17598914
references.citation: EBioMedicine. 2015 Jul 29;2(9):1079-89
references.pmid: 26501106
references.citation: Trends Genet. 2009 May;25(5):203-9
references.pmid: 19361881
references.citation: Bioinformatics. 2007 May 1;23(9):1061-7
references.pmid: 17332020
references.citation: J Mol Evol. 2003 Feb;56(2):151-61
references.pmid: 12574861
references.citation: Nucleic Acids Res. 2004;32(5):1792-7
references.pmid: 15034147
references.citation: Nucleic Acids Res. 2002 Apr 1;30(7):1575-84
references.pmid: 11917018
references.citation: Proc Natl Acad Sci U S A. 2003 Apr 15;100(8):4678-83
references.pmid: 12682299
references.citation: Mol Biol Evol. 2006 Sep;23(9):1670-80
references.pmid: 16754641
references.citation: Nucleic Acids Res. 2012 Jan;40(Database issue):D1100-7
references.pmid: 21948594
references.citation: PLoS One. 2010;5(8):e11935
references.pmid: 20808905
references.citation: BMC Evol Biol. 2009;9:23
references.pmid: 19175938
references.citation: Annu Rev Genet. 2011;45:1-20
references.pmid: 21721943
references.citation: Nucleic Acids Res. 2015 Jan;43(Database issue):D662-9
references.pmid: 25352552
references.citation: Int J Parasitol. 2009 Apr;39(5):533-9
references.pmid: 18992249
references.citation: N Z Vet J. 2006 Feb;54(1):47-9
references.pmid: 16528395
references.citation: Proteins. 2005 Mar 1;58(4):950-4
references.pmid: 15657927
references.citation: Proteins. 2006 Feb 1;62(2):371-80
references.pmid: 16315289
references.citation: Genome Res. 2006 Sep;16(9):1182-90
references.pmid: 16902084
references.citation: N Engl J Med. 2007 Sep 6;357(10):1018-27
references.pmid: 17804846
references.citation: Curr Opin Biotechnol. 1999 Dec;10(6):571-8
references.pmid: 10600691
references.citation: Neurobiol Aging. 1999 Sep-Oct;20(5):479-86
references.pmid: 10638521
references.citation: Nucleic Acids Res. 2014 Jan;42(Database issue):D1083-90
references.pmid: 24214965
references.citation: Mol Biol Evol. 2005 Jun;22(6):1365-74
references.pmid: 15758206
references.citation: Proteins. 2007 Apr 1;67(1):53-64
references.pmid: 17243179