6EEE

X-ray crystal structure of Pf-M17 in complex with inhibitor (6k) and regulatory zinc ion

6EEE の概要

• エントリーDOI: 10.2210/pdb6eee/pdb
• 分子名称: M17 LEUCYL-AMINOPEPTIDASE, (1R,2r,3S,5R,7R)-N-[(1R)-2-(hydroxyamino)-2-oxo-1-(3',4',5'-trifluoro[1,1'-biphenyl]-4-yl)ethyl]tricyclo[3.3.1.1~3,7~]decane-2-carboxamide, CARBONATE ION, ... (10 entities in total)
• 機能のキーワード: m17 leucyl-aminopeptidase, protease, inhibitor, hydroxamic acid, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• 由来する生物種: Plasmodium falciparum (isolate HB3)
• タンパク質・核酸の鎖数: 12
• 化学式量合計: 707993.05

構造登録者

Drinkwater, N.,McGowan, S. (登録日: 2018-08-13, 公開日: 2018-12-26, 最終更新日: 2024-03-13)

主引用文献

Vinh, N.B.,Drinkwater, N.,Malcolm, T.R.,Kassiou, M.,Lucantoni, L.,Grin, P.M.,Butler, G.S.,Duffy, S.,Overall, C.M.,Avery, V.M.,Scammells, P.J.,McGowan, S.
Hydroxamic Acid Inhibitors Provide Cross-Species Inhibition of Plasmodium M1 and M17 Aminopeptidases.
J. Med. Chem., 62:622-640, 2019

PubMed Abstract: There is an urgent clinical need for antimalarial compounds that target malaria caused by both Plasmodium falciparum and Plasmodium vivax. The M1 and M17 metalloexopeptidases play key roles in Plasmodium hemoglobin digestion and are validated drug targets. We used a multitarget strategy to rationally design inhibitors capable of potent inhibition of the M1 and M17 aminopeptidases from both P. falciparum ( Pf-M1 and Pf-M17) and P. vivax ( Pv-M1 and Pv-M17). The novel chemical series contains a hydroxamic acid zinc binding group to coordinate catalytic zinc ion/s, and a variety of hydrophobic groups to probe the S1' pockets of the four target enzymes. Structural characterization by cocrystallization showed that selected compounds utilize new and unexpected binding modes; most notably, compounds substituted with bulky hydrophobic substituents displace the Pf-M17 catalytic zinc ion. Excitingly, key compounds of the series potently inhibit all four molecular targets and show antimalarial activity comparable to current clinical candidates.

PubMed: 30537832
DOI: 10.1021/acs.jmedchem.8b01310

実験手法

X-RAY DIFFRACTION (2.3 Å)