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Basis for drug selectivity of plasmepsin IX and X inhibition in Plasmodium falciparum and vivax.
Hodder, Anthony N; Christensen, Janni; Scally, Stephen; Triglia, Tony; Ngo, Anna; Birkinshaw, Richard W; Bailey, Brodie; Favuzza, Paola; Dietrich, Melanie H; Tham, Wai-Hong; Czabotar, Peter E; Lowes, Kym; Guo, Zhuyan; Murgolo, Nicholas; Lera Ruiz, Manuel de; McCauley, John A; Sleebs, Brad E; Olsen, David; Cowman, Alan F.
Afiliação
  • Hodder AN; The Walter and Eliza Hall Institute of Medical Research, Parkville 3052 VIC, Australia; University of Melbourne, Melbourne, 3010 VIC, Australia.
  • Christensen J; The Walter and Eliza Hall Institute of Medical Research, Parkville 3052 VIC, Australia; University of Melbourne, Melbourne, 3010 VIC, Australia.
  • Scally S; The Walter and Eliza Hall Institute of Medical Research, Parkville 3052 VIC, Australia; University of Melbourne, Melbourne, 3010 VIC, Australia.
  • Triglia T; The Walter and Eliza Hall Institute of Medical Research, Parkville 3052 VIC, Australia.
  • Ngo A; The Walter and Eliza Hall Institute of Medical Research, Parkville 3052 VIC, Australia.
  • Birkinshaw RW; The Walter and Eliza Hall Institute of Medical Research, Parkville 3052 VIC, Australia; University of Melbourne, Melbourne, 3010 VIC, Australia.
  • Bailey B; The Walter and Eliza Hall Institute of Medical Research, Parkville 3052 VIC, Australia; University of Melbourne, Melbourne, 3010 VIC, Australia.
  • Favuzza P; The Walter and Eliza Hall Institute of Medical Research, Parkville 3052 VIC, Australia; University of Melbourne, Melbourne, 3010 VIC, Australia.
  • Dietrich MH; The Walter and Eliza Hall Institute of Medical Research, Parkville 3052 VIC, Australia; University of Melbourne, Melbourne, 3010 VIC, Australia.
  • Tham WH; The Walter and Eliza Hall Institute of Medical Research, Parkville 3052 VIC, Australia; University of Melbourne, Melbourne, 3010 VIC, Australia.
  • Czabotar PE; The Walter and Eliza Hall Institute of Medical Research, Parkville 3052 VIC, Australia; University of Melbourne, Melbourne, 3010 VIC, Australia.
  • Lowes K; The Walter and Eliza Hall Institute of Medical Research, Parkville 3052 VIC, Australia.
  • Guo Z; Merck & Co., Inc, 770 Sumneytown Pike, West Point, PA 19486, USA.
  • Murgolo N; Merck & Co., Inc, 770 Sumneytown Pike, West Point, PA 19486, USA.
  • Lera Ruiz M; Merck & Co., Inc, 770 Sumneytown Pike, West Point, PA 19486, USA.
  • McCauley JA; Merck & Co., Inc, 770 Sumneytown Pike, West Point, PA 19486, USA.
  • Sleebs BE; The Walter and Eliza Hall Institute of Medical Research, Parkville 3052 VIC, Australia; University of Melbourne, Melbourne, 3010 VIC, Australia.
  • Olsen D; Merck & Co., Inc, 770 Sumneytown Pike, West Point, PA 19486, USA.
  • Cowman AF; The Walter and Eliza Hall Institute of Medical Research, Parkville 3052 VIC, Australia; University of Melbourne, Melbourne, 3010 VIC, Australia. Electronic address: cowman@wehi.edu.au.
Structure ; 30(7): 947-961.e6, 2022 07 07.
Article em En | MEDLINE | ID: mdl-35460613
Plasmepsins IX (PMIX) and X (PMX) are essential aspartyl proteases for Plasmodium spp. egress, invasion, and development. WM4 and WM382 inhibit PMIX and PMX in Plasmodium falciparum and P. vivax. WM4 inhibits PMX, while WM382 is a dual inhibitor of PMIX and PMX. To understand their function, we identified protein substrates. Enzyme kinetic and structural analyses identified interactions responsible for drug specificity. PMIX and PMX have similar substrate specificity; however, there are distinct differences for peptide and protein substrates. Differences in WM4 and WM382 binding for PMIX and PMX map to variations in the S' region and engagement of the active site S3 pocket. Structures of PMX reveal interactions and mechanistic detail of drug binding important for development of clinical candidates against these targets.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Plasmodium falciparum / Ácido Aspártico Endopeptidases Idioma: En Revista: Structure Assunto da revista: BIOLOGIA MOLECULAR / BIOQUIMICA / BIOTECNOLOGIA Ano de publicação: 2022 Tipo de documento: Article País de afiliação: Austrália
Texto completo
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Plasmodium falciparum / Ácido Aspártico Endopeptidases Idioma: En Revista: Structure Assunto da revista: BIOLOGIA MOLECULAR / BIOQUIMICA / BIOTECNOLOGIA Ano de publicação: 2022 Tipo de documento: Article País de afiliação: Austrália