8FBQ
Crystal structure of Plasmodium vivax glycylpeptide N-tetradecanoyltransferase (N-myristoyltransferase, NMT) bound to myristoyl-CoA and inhibitor 12b
Summary for 8FBQ
| Entry DOI | 10.2210/pdb8fbq/pdb |
| Descriptor | Glycylpeptide N-tetradecanoyltransferase, TETRAETHYLENE GLYCOL, TRIETHYLENE GLYCOL, ... (12 entities in total) |
| Functional Keywords | enzyme, inhibitor, complex, structural genomics, seattle structural genomics center for infectious disease, ssgcid, transferase, transferase-inhibitor complex, transferase/inhibitor |
| Biological source | Plasmodium vivax |
| Total number of polymer chains | 1 |
| Total formula weight | 48454.53 |
| Authors | Fenwick, M.K.,Staker, B.L.,Lovell, S.W.,Phan, I.Q.,Early, J.,Myler, P.J.,Seattle Structural Genomics Center for Infectious Disease (SSGCID) (deposition date: 2022-11-29, release date: 2023-10-18) |
| Primary citation | Rodriguez-Hernandez, D.,Vijayan, K.,Zigweid, R.,Fenwick, M.K.,Sankaran, B.,Roobsoong, W.,Sattabongkot, J.,Glennon, E.K.K.,Myler, P.J.,Sunnerhagen, P.,Staker, B.L.,Kaushansky, A.,Grotli, M. Identification of potent and selective N-myristoyltransferase inhibitors of Plasmodium vivax liver stage hypnozoites and schizonts. Nat Commun, 14:5408-5408, 2023 Cited by PubMed Abstract: Drugs targeting multiple stages of the Plasmodium vivax life cycle are needed to reduce the health and economic burdens caused by malaria worldwide. N-myristoyltransferase (NMT) is an essential eukaryotic enzyme and a validated drug target for combating malaria. However, previous PvNMT inhibitors have failed due to their low selectivity over human NMTs. Herein, we apply a structure-guided hybridization approach combining chemical moieties of previously reported NMT inhibitors to develop the next generation of PvNMT inhibitors. A high-resolution crystal structure of PvNMT bound to a representative selective hybrid compound reveals a unique binding site architecture that includes a selective conformation of a key tyrosine residue. The hybridized compounds significantly decrease P. falciparum blood-stage parasite load and consistently exhibit dose-dependent inhibition of P. vivax liver stage schizonts and hypnozoites. Our data demonstrate that hybridized NMT inhibitors can be multistage antimalarials, targeting dormant and developing forms of liver and blood stage. PubMed: 37669940DOI: 10.1038/s41467-023-41119-7 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.65 Å) |
Structure validation
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