| Structural highlights
6mb1 is a 3 chain structure with sequence from Haemamoeba vivax. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Ligands: | , , , , |
| Gene: | PVC01_130042700, PVP01_1336100 (Haemamoeba vivax) |
| Activity: | Glycylpeptide N-tetradecanoyltransferase, with EC number 2.3.1.97 |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Function
[A0A1G4HIY1_PLAVI] Adds a myristoyl group to the N-terminal glycine residue of certain cellular proteins.[RuleBase:RU000586]
Publication Abstract from PubMed
The attachment of myristate to the N-terminal glycine of certain proteins is largely a co-translational modification catalyzed by N-myristoyltransferase (NMT), and involved in protein membrane-localization. Pathogen NMT is a validated therapeutic target in numerous infectious diseases including malaria. In Plasmodium falciparum, NMT substrates are important in essential processes including parasite gliding motility and host cell invasion. Here, we generated parasites resistant to a particular NMT inhibitor series and show that resistance in an in vitro parasite growth assay is mediated by a single amino acid substitution in the NMT substrate-binding pocket. The basis of resistance was validated and analyzed with a structure-guided approach using crystallography, in combination with enzyme activity, stability, and surface plasmon resonance assays, allowing identification of another inhibitor series unaffected by this substitution. We suggest that resistance studies incorporated early in the drug development process help selection of drug combinations to impede rapid evolution of parasite resistance.
Structure-Guided Identification of Resistance Breaking Antimalarial NMyristoyltransferase Inhibitors.,Schlott AC, Mayclin S, Reers AR, Coburn-Flynn O, Bell AS, Green J, Knuepfer E, Charter D, Bonnert R, Campo B, Burrows J, Lyons-Abbott S, Staker BL, Chung CW, Myler PJ, Fidock DA, Tate EW, Holder AA Cell Chem Biol. 2019 Apr 9. pii: S2451-9456(19)30111-4. doi:, 10.1016/j.chembiol.2019.03.015. PMID:31080074[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Schlott AC, Mayclin S, Reers AR, Coburn-Flynn O, Bell AS, Green J, Knuepfer E, Charter D, Bonnert R, Campo B, Burrows J, Lyons-Abbott S, Staker BL, Chung CW, Myler PJ, Fidock DA, Tate EW, Holder AA. Structure-Guided Identification of Resistance Breaking Antimalarial NMyristoyltransferase Inhibitors. Cell Chem Biol. 2019 Apr 9. pii: S2451-9456(19)30111-4. doi:, 10.1016/j.chembiol.2019.03.015. PMID:31080074 doi:http://dx.doi.org/10.1016/j.chembiol.2019.03.015
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