Database of articles cited by EMDB/PDB/SASBDB data

Keywords
Structure methods	All X-ray diffraction NMR electron microscopy small angle scattering neutron diffraction fiber diffraction powder diffraction infrared spectroscopy EPR fluorescence transfer theoretical model Hybrid
Author
Journal
IF	>30 >20 >10 >5 all

Title	Inhibition of falcilysin from Plasmodium falciparum by interference with its closed-to-open dynamic transition.
Journal, issue, pages	Commun Biol, Vol. 7, Issue 1, Page 1070, Year 2024
Publish date	Aug 31, 2024
Authors	Jianqing Lin / Xinfu Yan / Zara Chung / Chong Wai Liew / Abbas El Sahili / Evgeniya V Pechnikova / Peter R Preiser / Zbynek Bozdech / Yong-Gui Gao / Julien Lescar /
PubMed Abstract	In the absence of an efficacious vaccine, chemotherapy remains crucial to prevent and treat malaria. Given its key role in haemoglobin degradation, falcilysin constitutes an attractive target. Here, ...In the absence of an efficacious vaccine, chemotherapy remains crucial to prevent and treat malaria. Given its key role in haemoglobin degradation, falcilysin constitutes an attractive target. Here, we reveal the mechanism of enzymatic inhibition of falcilysin by MK-4815, an investigational new drug with potent antimalarial activity. Using X-ray crystallography, we determine two binary complexes of falcilysin in a closed state, bound with peptide substrates from the haemoglobin α and β chains respectively. An antiparallel β-sheet is formed between the substrate and enzyme, accounting for sequence-independent recognition at positions P2 and P1. In contrast, numerous contacts favor tyrosine and phenylalanine at the P1' position of the substrate. Cryo-EM studies reveal a majority of unbound falcilysin molecules adopting an open conformation. Addition of MK-4815 shifts about two-thirds of falcilysin molecules to a closed state. These structures give atomic level pictures of the proteolytic cycle, in which falcilysin interconverts between a closed state conducive to proteolysis, and an open conformation amenable to substrate diffusion and products release. MK-4815 and quinolines bind to an allosteric pocket next to a hinge region of falcilysin and hinders this dynamic transition. These data should inform the design of potent inhibitors of falcilysin to combat malaria.
External links	Commun Biol / PubMed:39217277 / PubMed Central
Methods	EM (single particle) / X-ray diffraction
Resolution	1.86 - 3.5 Å
Structure data	37938 8wyt EMDB-37938, PDB-8wyt: Partially closed Falcilysin bound to MK-4815, from MK-4815-treated dataset Method: EM (single particle) / Resolution: 2.7 Å 37939 8wyu EMDB-37939, PDB-8wyu: Open Falcilysin, from MK-4815-treated dataset Method: EM (single particle) / Resolution: 3.2 Å 37940 8wyx EMDB-37940, PDB-8wyx: Partially closed falcilysin, from free falcilysin dataset Method: EM (single particle) / Resolution: 3.5 Å 37941 8wyy EMDB-37941, PDB-8wyy: Open falcilysin, from free falcilysin dataset Method: EM (single particle) / Resolution: 3.1 Å PDB-8wxw: Falcilysin in complex with hemoglobin alpha chain peptide Method: X-RAY DIFFRACTION / Resolution: 1.86 Å PDB-8wxz: Falcilysin in complex with hemoglobin beta chain peptide Method: X-RAY DIFFRACTION / Resolution: 2.3 Å
Chemicals	ChemComp-GOL: GLYCEROL ChemComp-EDO: 1,2-ETHANEDIOL ChemComp-ZN: Unknown entry ChemComp-CL: Unknown entry ChemComp-HOH: WATER ChemComp-PEG: DI(HYDROXYETHYL)ETHER ChemComp-ACY: ACETIC ACID ChemComp-H8F: 2-(aminomethyl)-3,5-ditert-butyl-phenol
Source	plasmodium falciparum 3d7 (eukaryote) homo sapiens (human)
Keywords	HYDROLASE / falcilysin-substrate complex / inactive mutant / falcilysin partially closed conformation / MK-4815 binding / falcilysin open conformation