8VKA

Crystal structure of Plasmodium vivax glycylpeptide N-tetradecanoyltransferase (N-myristoyltransferase, NMT) bound to myristoyl-CoA and inhibitor 9c

これはPDB形式変換不可エントリーです。

8VKA の概要

• エントリーDOI: 10.2210/pdb8vka/pdb
• 分子名称: 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)
• 機能のキーワード: enzyme, inhibitor, complex, structural genomics, seattle structural genomics center for infectious disease, ssgcid, transferase
• 由来する生物種: Plasmodium vivax Sal-1
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 141628.36

構造登録者

Fenwick, M.K.,Staker, B.L.,Phan, I.Q.,Early, J.,Myler, P.J.,Seattle Structural Genomics Center for Infectious Disease (SSGCID) (登録日: 2024-01-08, 公開日: 2024-07-17)

主引用文献

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

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: 38680035
DOI: 10.1021/acs.jmedchem.4c00168

実験手法

X-RAY DIFFRACTION (1.97 Å)