Structures of DPAGT1 explain glycosylation disease mechanisms and advance TB antibiotic design
Protein N-glycosylation is a widespread post-translational modification. The first committed step in this process is catalysed by dolichyl-phosphate N-acetylglucosamine-phosphotransferase DPAGT1 (GPT/E.C. 2.7.8.15). Missense DPAGT1 variants cause congenital myasthenic syndrome and disorders of glyco...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Journal article |
| Language: | English |
| Published: |
Elsevier
2018
|
| _version_ | 1797068360595275776 |
|---|---|
| author | Dong, YY Wang, H Pike, ACW Cochrane, SA Hamedzadeh, S Wyszyński, FJ Bushell, SR Royer, SF Widdick, DA Sajid, A Boshoff, HI Park, Y Lucas, R Liu, W-M Lee, SS Machida, T Minall, L Mehmood, S Belaya, K Liu, W-W Chu, A Shrestha, L Mukhopadhyay, SMM Strain-Damerell, C Chalk, R Burgess-Brown, NA Bibb, MJ Barry, CE Robinson, CV Beeson, D Davis, BG Carpenter, EP |
| author_facet | Dong, YY Wang, H Pike, ACW Cochrane, SA Hamedzadeh, S Wyszyński, FJ Bushell, SR Royer, SF Widdick, DA Sajid, A Boshoff, HI Park, Y Lucas, R Liu, W-M Lee, SS Machida, T Minall, L Mehmood, S Belaya, K Liu, W-W Chu, A Shrestha, L Mukhopadhyay, SMM Strain-Damerell, C Chalk, R Burgess-Brown, NA Bibb, MJ Barry, CE Robinson, CV Beeson, D Davis, BG Carpenter, EP |
| author_sort | Dong, YY |
| collection | OXFORD |
| description | Protein N-glycosylation is a widespread post-translational modification. The first committed step in this process is catalysed by dolichyl-phosphate N-acetylglucosamine-phosphotransferase DPAGT1 (GPT/E.C. 2.7.8.15). Missense DPAGT1 variants cause congenital myasthenic syndrome and disorders of glycosylation. In addition, naturally-occurring bactericidal nucleoside analogues such as tunicamycin are toxic to eukaryotes due to DPAGT1 inhibition, preventing their clinical use. Our structures of DPAGT1 with the substrate UDP-GlcNAc and tunicamycin reveal substrate binding modes, suggest a mechanism of catalysis, provide an understanding of how mutations modulate activity (thus causing disease) and allow design of non-toxic “lipid-altered” tunicamycins. The structure-tuned activity of these analogues against several bacterial targets allowed the design of potent antibiotics for Mycobacterium tuberculosis, enabling treatment in vitro, in cellulo and in vivo, providing a promising new class of antimicrobial drug. |
| first_indexed | 2024-03-06T22:09:39Z |
| format | Journal article |
| id | oxford-uuid:515d9416-1e72-4e91-87e4-39eb4f426368 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-06T22:09:39Z |
| publishDate | 2018 |
| publisher | Elsevier |
| record_format | dspace |
| spelling | oxford-uuid:515d9416-1e72-4e91-87e4-39eb4f4263682022-03-26T16:19:12ZStructures of DPAGT1 explain glycosylation disease mechanisms and advance TB antibiotic designJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:515d9416-1e72-4e91-87e4-39eb4f426368EnglishSymplectic Elements at OxfordElsevier2018Dong, YYWang, HPike, ACWCochrane, SAHamedzadeh, SWyszyński, FJBushell, SRRoyer, SFWiddick, DASajid, ABoshoff, HIPark, YLucas, RLiu, W-MLee, SSMachida, TMinall, LMehmood, SBelaya, KLiu, W-WChu, AShrestha, LMukhopadhyay, SMMStrain-Damerell, CChalk, RBurgess-Brown, NABibb, MJBarry, CERobinson, CVBeeson, DDavis, BGCarpenter, EPProtein N-glycosylation is a widespread post-translational modification. The first committed step in this process is catalysed by dolichyl-phosphate N-acetylglucosamine-phosphotransferase DPAGT1 (GPT/E.C. 2.7.8.15). Missense DPAGT1 variants cause congenital myasthenic syndrome and disorders of glycosylation. In addition, naturally-occurring bactericidal nucleoside analogues such as tunicamycin are toxic to eukaryotes due to DPAGT1 inhibition, preventing their clinical use. Our structures of DPAGT1 with the substrate UDP-GlcNAc and tunicamycin reveal substrate binding modes, suggest a mechanism of catalysis, provide an understanding of how mutations modulate activity (thus causing disease) and allow design of non-toxic “lipid-altered” tunicamycins. The structure-tuned activity of these analogues against several bacterial targets allowed the design of potent antibiotics for Mycobacterium tuberculosis, enabling treatment in vitro, in cellulo and in vivo, providing a promising new class of antimicrobial drug. |
| spellingShingle | Dong, YY Wang, H Pike, ACW Cochrane, SA Hamedzadeh, S Wyszyński, FJ Bushell, SR Royer, SF Widdick, DA Sajid, A Boshoff, HI Park, Y Lucas, R Liu, W-M Lee, SS Machida, T Minall, L Mehmood, S Belaya, K Liu, W-W Chu, A Shrestha, L Mukhopadhyay, SMM Strain-Damerell, C Chalk, R Burgess-Brown, NA Bibb, MJ Barry, CE Robinson, CV Beeson, D Davis, BG Carpenter, EP Structures of DPAGT1 explain glycosylation disease mechanisms and advance TB antibiotic design |
| title | Structures of DPAGT1 explain glycosylation disease mechanisms and advance TB antibiotic design |
| title_full | Structures of DPAGT1 explain glycosylation disease mechanisms and advance TB antibiotic design |
| title_fullStr | Structures of DPAGT1 explain glycosylation disease mechanisms and advance TB antibiotic design |
| title_full_unstemmed | Structures of DPAGT1 explain glycosylation disease mechanisms and advance TB antibiotic design |
| title_short | Structures of DPAGT1 explain glycosylation disease mechanisms and advance TB antibiotic design |
| title_sort | structures of dpagt1 explain glycosylation disease mechanisms and advance tb antibiotic design |
| work_keys_str_mv | AT dongyy structuresofdpagt1explainglycosylationdiseasemechanismsandadvancetbantibioticdesign AT wangh structuresofdpagt1explainglycosylationdiseasemechanismsandadvancetbantibioticdesign AT pikeacw structuresofdpagt1explainglycosylationdiseasemechanismsandadvancetbantibioticdesign AT cochranesa structuresofdpagt1explainglycosylationdiseasemechanismsandadvancetbantibioticdesign AT hamedzadehs structuresofdpagt1explainglycosylationdiseasemechanismsandadvancetbantibioticdesign AT wyszynskifj structuresofdpagt1explainglycosylationdiseasemechanismsandadvancetbantibioticdesign AT bushellsr structuresofdpagt1explainglycosylationdiseasemechanismsandadvancetbantibioticdesign AT royersf structuresofdpagt1explainglycosylationdiseasemechanismsandadvancetbantibioticdesign AT widdickda structuresofdpagt1explainglycosylationdiseasemechanismsandadvancetbantibioticdesign AT sajida structuresofdpagt1explainglycosylationdiseasemechanismsandadvancetbantibioticdesign AT boshoffhi structuresofdpagt1explainglycosylationdiseasemechanismsandadvancetbantibioticdesign AT parky structuresofdpagt1explainglycosylationdiseasemechanismsandadvancetbantibioticdesign AT lucasr structuresofdpagt1explainglycosylationdiseasemechanismsandadvancetbantibioticdesign AT liuwm structuresofdpagt1explainglycosylationdiseasemechanismsandadvancetbantibioticdesign AT leess structuresofdpagt1explainglycosylationdiseasemechanismsandadvancetbantibioticdesign AT machidat structuresofdpagt1explainglycosylationdiseasemechanismsandadvancetbantibioticdesign AT minalll structuresofdpagt1explainglycosylationdiseasemechanismsandadvancetbantibioticdesign AT mehmoods structuresofdpagt1explainglycosylationdiseasemechanismsandadvancetbantibioticdesign AT belayak structuresofdpagt1explainglycosylationdiseasemechanismsandadvancetbantibioticdesign AT liuww structuresofdpagt1explainglycosylationdiseasemechanismsandadvancetbantibioticdesign AT chua structuresofdpagt1explainglycosylationdiseasemechanismsandadvancetbantibioticdesign AT shresthal structuresofdpagt1explainglycosylationdiseasemechanismsandadvancetbantibioticdesign AT mukhopadhyaysmm structuresofdpagt1explainglycosylationdiseasemechanismsandadvancetbantibioticdesign AT straindamerellc structuresofdpagt1explainglycosylationdiseasemechanismsandadvancetbantibioticdesign AT chalkr structuresofdpagt1explainglycosylationdiseasemechanismsandadvancetbantibioticdesign AT burgessbrownna structuresofdpagt1explainglycosylationdiseasemechanismsandadvancetbantibioticdesign AT bibbmj structuresofdpagt1explainglycosylationdiseasemechanismsandadvancetbantibioticdesign AT barryce structuresofdpagt1explainglycosylationdiseasemechanismsandadvancetbantibioticdesign AT robinsoncv structuresofdpagt1explainglycosylationdiseasemechanismsandadvancetbantibioticdesign AT beesond structuresofdpagt1explainglycosylationdiseasemechanismsandadvancetbantibioticdesign AT davisbg structuresofdpagt1explainglycosylationdiseasemechanismsandadvancetbantibioticdesign AT carpenterep structuresofdpagt1explainglycosylationdiseasemechanismsandadvancetbantibioticdesign |