8vkb

Crystal structure of Plasmodium vivax glycylpeptide N-tetradecanoyltransferase (N-myristoyltransferase, NMT) bound to myristoyl-CoA and inhibitor 10b

spinqualitylabelsall models 8vkb, resolution 2.43Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 8vkb is a 3 chain structure with sequence from Plasmodium vivax Sal-1. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.43Å Ligands: 1PE, A1AB8, CL, GOL, MYA, P6G Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function A5K1A2_PLAVS Adds a myristoyl group to the N-terminal glycine residue of certain cellular proteins (By similarity).[RuleBase:RU000586] Publication Abstract from PubMed N-myristoyltransferase (NMT) is a promising antimalarial drug target. Despite biochemical similarities between Plasmodium vivax and human NMTs, our recent research demonstrated that high selectivity is achievable. Herein, we report PvNMT-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 A, 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. Exploring Subsite Selectivity within Plasmodium vivax N-Myristoyltransferase Using Pyrazole-Derived Inhibitors.,Rodriguez-Hernandez D, Fenwick MK, Zigweid R, Sankaran B, Myler PJ, Sunnerhagen P, Kaushansky A, Staker BL, Grotli M J Med Chem. 2024 May 9;67(9):7312-7329. doi: 10.1021/acs.jmedchem.4c00168. Epub , 2024 Apr 29. PMID:38680035 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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