6MB1

Crystal structure of N-myristoyl transferase (NMT) from Plasmodium vivax in complex with inhibitor IMP-1002

Summary for 6MB1

• Entry DOI: 10.2210/pdb6mb1/pdb
• Descriptor: Glycylpeptide N-tetradecanoyltransferase, TETRADEC-13-YNOIC ACID - COA THIOESTER, 1-(5-{4-fluoro-2-[2-(1,3,5-trimethyl-1H-pyrazol-4-yl)ethoxy]phenyl}-1-methyl-1H-indazol-3-yl)-N,N-dimethylmethanamine, ... (7 entities in total)
• Functional Keywords: ssgcid, glycylpeptide n-tetradecanoyltransferase, n-myristoyltransferase, nmt, structural genomics, seattle structural genomics center for infectious disease, transferase
• Biological source: Plasmodium vivax
• Total number of polymer chains: 3
• Total formula weight: 146679.99

Authors

Seattle Structural Genomics Center for Infectious Disease,Seattle Structural Genomics Center for Infectious Disease (SSGCID) (deposition date: 2018-08-29, release date: 2019-06-05, Last modification date: 2024-03-13)

Primary citation

Schlott, A.C.,Mayclin, S.,Reers, A.R.,Coburn-Flynn, O.,Bell, A.S.,Green, J.,Knuepfer, E.,Charter, D.,Bonnert, R.,Campo, B.,Burrows, J.,Lyons-Abbott, S.,Staker, B.L.,Chung, C.W.,Myler, P.J.,Fidock, D.A.,Tate, E.W.,Holder, A.A.
Structure-Guided Identification of Resistance Breaking Antimalarial N‐Myristoyltransferase Inhibitors.
Cell Chem Biol, 26:991-, 2019

PubMed Abstract: 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.

PubMed: 31080074
DOI: 10.1016/j.chembiol.2019.03.015

Experimental method

X-RAY DIFFRACTION (1.5 Å)