8VKA
Crystal structure of Plasmodium vivax glycylpeptide N-tetradecanoyltransferase (N-myristoyltransferase, NMT) bound to myristoyl-CoA and inhibitor 9c
This is a non-PDB format compatible entry.
Summary for 8VKA
| Entry DOI | 10.2210/pdb8vka/pdb |
| Descriptor | Glycylpeptide N-tetradecanoyltransferase, TETRADECANOYL-COA, N-[1,5-dimethyl-4-(2-{[(2M)-2'-(piperazin-1-yl)[2,4'-bipyridin]-3-yl]oxy}ethyl)-1H-pyrazole-3-carbonyl]glycine, ... (9 entities in total) |
| Functional Keywords | enzyme, inhibitor, complex, structural genomics, seattle structural genomics center for infectious disease, ssgcid, transferase |
| Biological source | Plasmodium vivax Sal-1 |
| Total number of polymer chains | 3 |
| Total formula weight | 141628.36 |
| Authors | Fenwick, M.K.,Staker, B.L.,Phan, I.Q.,Early, J.,Myler, P.J.,Seattle Structural Genomics Center for Infectious Disease (SSGCID) (deposition date: 2024-01-08, release date: 2024-07-17) |
| Primary citation | Rodriguez-Hernandez, D.,Fenwick, M.K.,Zigweid, R.,Sankaran, B.,Myler, P.J.,Sunnerhagen, P.,Kaushansky, A.,Staker, B.L.,Grotli, M. Exploring Subsite Selectivity within Plasmodium vivax N -Myristoyltransferase Using Pyrazole-Derived Inhibitors. J.Med.Chem., 67:7312-7329, 2024 Cited by PubMed Abstract: -myristoyltransferase (NMT) is a promising antimalarial drug target. Despite biochemical similarities between and human NMTs, our recent research demonstrated that high selectivity is achievable. Herein, we report NMT-inhibiting compounds aimed at identifying novel mechanisms of selectivity. Various functional groups are appended to a pyrazole moiety in the inhibitor to target a pocket formed beneath the peptide binding cleft. The inhibitor core group polarity, lipophilicity, and size are also varied to probe the water structure near a channel. Selectivity index values range from 0.8 to 125.3. Cocrystal structures of two selective compounds, determined at 1.97 and 2.43 Å, show that extensions bind the targeted pocket but with different stabilities. A bulky naphthalene moiety introduced into the core binds next to instead of displacing protein-bound waters, causing a shift in the inhibitor position and expanding the binding site. Our structure-activity data provide a conceptual foundation for guiding future inhibitor optimizations. PubMed: 38680035DOI: 10.1021/acs.jmedchem.4c00168 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.97 Å) |
Structure validation
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