Myler PJ

References (4)

Title : Increasing the structural coverage of tuberculosis drug targets - Baugh_2015_Tuberculosis.(Edinb)_95_142
Author(s) : Baugh L , Phan I , Begley DW , Clifton MC , Armour B , Dranow DM , Taylor BM , Muruthi MM , Abendroth J , Fairman JW , Fox D, 3rd , Dieterich SH , Staker BL , Gardberg AS , Choi R , Hewitt SN , Napuli AJ , Myers J , Barrett LK , Zhang Y , Ferrell M , Mundt E , Thompkins K , Tran N , Lyons-Abbott S , Abramov A , Sekar A , Serbzhinskiy D , Lorimer D , Buchko GW , Stacy R , Stewart LJ , Edwards TE , Van Voorhis WC , Myler PJ
Ref : Tuberculosis (Edinb) , 95 :142 , 2015
Abstract : High-resolution three-dimensional structures of essential Mycobacterium tuberculosis (Mtb) proteins provide templates for TB drug design, but are available for only a small fraction of the Mtb proteome. Here we evaluate an intra-genus "homolog-rescue" strategy to increase the structural information available for TB drug discovery by using mycobacterial homologs with conserved active sites. Of 179 potential TB drug targets selected for x-ray structure determination, only 16 yielded a crystal structure. By adding 1675 homologs from nine other mycobacterial species to the pipeline, structures representing an additional 52 otherwise intractable targets were solved. To determine whether these homolog structures would be useful surrogates in TB drug design, we compared the active sites of 106 pairs of Mtb and non-TB mycobacterial (NTM) enzyme homologs with experimentally determined structures, using three metrics of active site similarity, including superposition of continuous pharmacophoric property distributions. Pair-wise structural comparisons revealed that 19/22 pairs with >55% overall sequence identity had active site Calpha RMSD <1 A, >85% side chain identity, and >/=80% PSAPF (similarity based on pharmacophoric properties) indicating highly conserved active site shape and chemistry. Applying these results to the 52 NTM structures described above, 41 shared >55% sequence identity with the Mtb target, thus increasing the effective structural coverage of the 179 Mtb targets over three-fold (from 9% to 32%). The utility of these structures in TB drug design can be tested by designing inhibitors using the homolog structure and assaying the cognate Mtb enzyme; a promising test case, Mtb cytidylate kinase, is described. The homolog-rescue strategy evaluated here for TB is also generalizable to drug targets for other diseases.
ESTHER : Baugh_2015_Tuberculosis.(Edinb)_95_142
PubMedSearch : Baugh_2015_Tuberculosis.(Edinb)_95_142
PubMedID: 25613812
Gene_locus related to this paper: mycmm-b2hlx2 , mycs2-a0qvs8

Title : The genome sequence of Trypanosoma cruzi, etiologic agent of Chagas disease - El-Sayed_2005_Science_309_409
Author(s) : El-Sayed NM , Myler PJ , Bartholomeu DC , Nilsson D , Aggarwal G , Tran AN , Ghedin E , Worthey EA , Delcher AL , Blandin G , Westenberger SJ , Caler E , Cerqueira GC , Branche C , Haas B , Anupama A , Arner E , Aslund L , Attipoe P , Bontempi E , Bringaud F , Burton P , Cadag E , Campbell DA , Carrington M , Crabtree J , Darban H , da Silveira JF , de Jong P , Edwards K , Englund PT , Fazelina G , Feldblyum T , Ferella M , Frasch AC , Gull K , Horn D , Hou L , Huang Y , Kindlund E , Klingbeil M , Kluge S , Koo H , Lacerda D , Levin MJ , Lorenzi H , Louie T , Machado CR , McCulloch R , McKenna A , Mizuno Y , Mottram JC , Nelson S , Ochaya S , Osoegawa K , Pai G , Parsons M , Pentony M , Pettersson U , Pop M , Ramirez JL , Rinta J , Robertson L , Salzberg SL , Sanchez DO , Seyler A , Sharma R , Shetty J , Simpson AJ , Sisk E , Tammi MT , Tarleton R , Teixeira S , Van Aken S , Vogt C , Ward PN , Wickstead B , Wortman J , White O , Fraser CM , Stuart KD , Andersson B
Ref : Science , 309 :409 , 2005
Abstract : Whole-genome sequencing of the protozoan pathogen Trypanosoma cruzi revealed that the diploid genome contains a predicted 22,570 proteins encoded by genes, of which 12,570 represent allelic pairs. Over 50% of the genome consists of repeated sequences, such as retrotransposons and genes for large families of surface molecules, which include trans-sialidases, mucins, gp63s, and a large novel family (>1300 copies) of mucin-associated surface protein (MASP) genes. Analyses of the T. cruzi, T. brucei, and Leishmania major (Tritryp) genomes imply differences from other eukaryotes in DNA repair and initiation of replication and reflect their unusual mitochondrial DNA. Although the Tritryp lack several classes of signaling molecules, their kinomes contain a large and diverse set of protein kinases and phosphatases; their size and diversity imply previously unknown interactions and regulatory processes, which may be targets for intervention.
ESTHER : El-Sayed_2005_Science_309_409
PubMedSearch : El-Sayed_2005_Science_309_409
PubMedID: 16020725
Gene_locus related to this paper: tryb2-q6h9e3 , tryb2-q6ha27 , tryb2-q38cd5 , tryb2-q38cd6 , tryb2-q38cd7 , tryb2-q38dc1 , tryb2-q38de4 , tryb2-q38ds6 , tryb2-q38dx1 , tryb2-q380z6 , tryb2-q382l4 , tryb2-q383a9 , tryb2-q386e3 , tryb2-q387r7 , tryb2-q388n1 , tryb2-q389w3 , trybr-PEPTB , trycr-q4cq28 , trycr-q4cq94 , trycr-q4cq95 , trycr-q4cq96 , trycr-q4cqq5 , trycr-q4csm0 , trycr-q4cwv3 , trycr-q4cx66 , trycr-q4cxr6 , trycr-q4cyc3 , trycr-q4cyc5 , trycr-q4cyf6 , trycr-q4czy3 , trycr-q4d1s2 , trycr-q4d2n1 , trycr-q4d3a2 , trycr-q4d3x3 , trycr-q4d3y4 , trycr-q4d6h1 , trycr-q4d8h8 , trycr-q4d8h9 , trycr-q4d8i0 , trycr-q4d786 , trycr-q4d975 , trycr-q4da08 , trycr-q4dab1 , trycr-q4dap6 , trycr-q4dap7 , trycr-q4dbm2 , trycr-q4dbn1 , trycr-q4ddw7 , trycr-q4de42 , trycr-q4dhn8 , trycr-q4dkk8 , trycr-q4dkk9 , trycr-q4dm56 , trycr-q4dp03 , trycr-q4dqa6 , trycr-q4dry8 , trycr-q4dt91 , trycr-q4dvl8 , trycr-q4dvp1 , trycr-q4dvp2 , trycr-q4dw34 , trycr-q4dwm3 , trycr-q4dy49 , trycr-q4dy82 , trycr-q4dzp6 , trycr-q4e3m8 , trycr-q4e4t5 , trycr-q4e5d1 , trycr-q4e5z2 , trycr-q6y3z8 , trycr-Q94795 , trycr-TCPO

Title : Comparative genomics of trypanosomatid parasitic protozoa - El-Sayed_2005_Science_309_404
Author(s) : El-Sayed NM , Myler PJ , Blandin G , Berriman M , Crabtree J , Aggarwal G , Caler E , Renauld H , Worthey EA , Hertz-Fowler C , Ghedin E , Peacock C , Bartholomeu DC , Haas BJ , Tran AN , Wortman JR , Alsmark UC , Angiuoli S , Anupama A , Badger J , Bringaud F , Cadag E , Carlton JM , Cerqueira GC , Creasy T , Delcher AL , Djikeng A , Embley TM , Hauser C , Ivens AC , Kummerfeld SK , Pereira-Leal JB , Nilsson D , Peterson J , Salzberg SL , Shallom J , Silva JC , Sundaram J , Westenberger S , White O , Melville SE , Donelson JE , Andersson B , Stuart KD , Hall N
Ref : Science , 309 :404 , 2005
Abstract : A comparison of gene content and genome architecture of Trypanosoma brucei, Trypanosoma cruzi, and Leishmania major, three related pathogens with different life cycles and disease pathology, revealed a conserved core proteome of about 6200 genes in large syntenic polycistronic gene clusters. Many species-specific genes, especially large surface antigen families, occur at nonsyntenic chromosome-internal and subtelomeric regions. Retroelements, structural RNAs, and gene family expansion are often associated with syntenic discontinuities that-along with gene divergence, acquisition and loss, and rearrangement within the syntenic regions-have shaped the genomes of each parasite. Contrary to recent reports, our analyses reveal no evidence that these species are descended from an ancestor that contained a photosynthetic endosymbiont.
ESTHER : El-Sayed_2005_Science_309_404
PubMedSearch : El-Sayed_2005_Science_309_404
PubMedID: 16020724
Gene_locus related to this paper: tryb2-q382c1 , trycr-q4dhv2 , trycr-q4dpt2 , trycr-q4dpy4

Title : The genome of the kinetoplastid parasite, Leishmania major - Ivens_2005_Science_309_436
Author(s) : Ivens AC , Peacock CS , Worthey EA , Murphy L , Aggarwal G , Berriman M , Sisk E , Rajandream MA , Adlem E , Aert R , Anupama A , Apostolou Z , Attipoe P , Bason N , Bauser C , Beck A , Beverley SM , Bianchettin G , Borzym K , Bothe G , Bruschi CV , Collins M , Cadag E , Ciarloni L , Clayton C , Coulson RM , Cronin A , Cruz AK , Davies RM , De Gaudenzi J , Dobson DE , Duesterhoeft A , Fazelina G , Fosker N , Frasch AC , Fraser A , Fuchs M , Gabel C , Goble A , Goffeau A , Harris D , Hertz-Fowler C , Hilbert H , Horn D , Huang Y , Klages S , Knights A , Kube M , Larke N , Litvin L , Lord A , Louie T , Marra M , Masuy D , Matthews K , Michaeli S , Mottram JC , Muller-Auer S , Munden H , Nelson S , Norbertczak H , Oliver K , O'Neil S , Pentony M , Pohl TM , Price C , Purnelle B , Quail MA , Rabbinowitsch E , Reinhardt R , Rieger M , Rinta J , Robben J , Robertson L , Ruiz JC , Rutter S , Saunders D , Schafer M , Schein J , Schwartz DC , Seeger K , Seyler A , Sharp S , Shin H , Sivam D , Squares R , Squares S , Tosato V , Vogt C , Volckaert G , Wambutt R , Warren T , Wedler H , Woodward J , Zhou S , Zimmermann W , Smith DF , Blackwell JM , Stuart KD , Barrell B , Myler PJ
Ref : Science , 309 :436 , 2005
Abstract : Leishmania species cause a spectrum of human diseases in tropical and subtropical regions of the world. We have sequenced the 36 chromosomes of the 32.8-megabase haploid genome of Leishmania major (Friedlin strain) and predict 911 RNA genes, 39 pseudogenes, and 8272 protein-coding genes, of which 36% can be ascribed a putative function. These include genes involved in host-pathogen interactions, such as proteolytic enzymes, and extensive machinery for synthesis of complex surface glycoconjugates. The organization of protein-coding genes into long, strand-specific, polycistronic clusters and lack of general transcription factors in the L. major, Trypanosoma brucei, and Trypanosoma cruzi (Tritryp) genomes suggest that the mechanisms regulating RNA polymerase II-directed transcription are distinct from those operating in other eukaryotes, although the trypanosomatids appear capable of chromatin remodeling. Abundant RNA-binding proteins are encoded in the Tritryp genomes, consistent with active posttranscriptional regulation of gene expression.
ESTHER : Ivens_2005_Science_309_436
PubMedSearch : Ivens_2005_Science_309_436
PubMedID: 16020728
Gene_locus related to this paper: leima-e9ady6 , leima-L2464.12 , leima-L2802.02 , leima-OPB , leima-q4fw33 , leima-q4fwg8 , leima-q4fwj0 , leima-q4fya7 , leima-q4q0a1 , leima-q4q0t5 , leima-q4q0v0 , leima-q4q1h9 , leima-q4q2c9 , leima-q4q4j7 , leima-q4q4t6 , leima-q4q5j1 , leima-q4q6e9 , leima-q4q7v8 , leima-q4q8a8 , leima-q4q9g9 , leima-q4q080 , leima-q4q398 , leima-q4q615 , leima-q4q819 , leima-q4q871 , leima-q4q942 , leima-q4qae7 , leima-q4qb85 , leima-q4qdz7 , leima-q4qe26 , leima-q4qe31 , leima-q4qe85 , leima-q4qe86 , leima-q4qe87 , leima-q4qe90 , leima-q4qec8 , leima-q4qgz4 , leima-q4qgz5 , leima-q4qhs0 , leima-q4qj45