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 mechanism of potential antituberculosis compound lansoprazole sulfide.
Journal, issue, pages	Proc Natl Acad Sci U S A, Vol. 121, Issue 47, Page e2412780121, Year 2024
Publish date	Nov 19, 2024
Authors	Terezia Kovalova / Sylwia Król / Ana P Gamiz-Hernandez / Dan Sjöstrand / Ville R I Kaila / Peter Brzezinski / Martin Högbom /
PubMed Abstract	Tuberculosis is one of the most common causes of death worldwide, with a rapid emergence of multi-drug-resistant strains underscoring the need for new antituberculosis drugs. Recent studies indicate ...Tuberculosis is one of the most common causes of death worldwide, with a rapid emergence of multi-drug-resistant strains underscoring the need for new antituberculosis drugs. Recent studies indicate that lansoprazole-a known gastric proton pump inhibitor and its intracellular metabolite, lansoprazole sulfide (LPZS)-are potential antituberculosis compounds. Yet, their inhibitory mechanism and site of action still remain unknown. Here, we combine biochemical, computational, and structural approaches to probe the interaction of LPZS with the respiratory chain supercomplex IIIIV of , a close homolog of supercomplex. We show that LPZS binds to the Q cavity of the mycobacterial supercomplex, inhibiting the quinol substrate oxidation process and the activity of the enzyme. We solve high-resolution (2.6 Å) cryo-electron microscopy (cryo-EM) structures of the supercomplex with bound LPZS that together with microsecond molecular dynamics simulations, directed mutagenesis, and functional assays reveal key interactions that stabilize the inhibitor, but also how mutations can lead to the emergence of drug resistance. Our combined findings reveal an inhibitory mechanism of LPZS and provide a structural basis for drug development against tuberculosis.
External links	Proc Natl Acad Sci U S A / PubMed:39531492 / PubMed Central
Methods	EM (single particle)
Resolution	2.6 - 2.7 Å
Structure data	50752 9ftz EMDB-50752, PDB-9ftz: CIII2/CIV respiratory supercomplex from Mycobacterium smegmatis with lansoprazole sulfide Method: EM (single particle) / Resolution: 2.6 Å 50753 9fu0 EMDB-50753, PDB-9fu0: CIII2/CIV respiratory chain supercomplex from Mycobacterium smegmatis Method: EM (single particle) / Resolution: 2.7 Å
Chemicals	ChemComp-MQ9: MENAQUINONE-9 ChemComp, No image ChemComp-WUO: Unknown entry ChemComp-HEC: HEME C ChemComp-FES: FE2/S2 (INORGANIC) CLUSTER ChemComp-9YF: (2R)-2-(hexadecanoyloxy)-3-{[(S)-hydroxy{[(1R,2R,3R,4R,5R,6S)-2,3,4,5,6-pentahydroxycyclohexyl]oxy}phosphoryl]oxy}propyl (9S)-9-methyloctadecanoate ChemComp-7PH: (1R)-2-(dodecanoyloxy)-1-[(phosphonooxy)methyl]ethyl tetradecanoate ChemComp-IZL: [(2~{R})-3-[[(1~{S},2~{R},3~{S},4~{S},5~{R},6~{R})-2-[(2~{R},3~{S},4~{S},5~{S},6~{R})-6-[[(2~{S},3~{S},4~{S},5~{S},6~{R})-6-[[(2~{S},3~{S},4~{S},5~{S},6~{R})-6-(hydroxymethyl)-3-[(2~{R},3~{S},4~{S},5~{S},6~{R})-6-(hydroxymethyl)-3,4,5-tris(oxidanyl)oxan-2-yl]oxy-4,5-bis(oxidanyl)oxan-2-yl]oxymethyl]-3,4,5-tris(oxidanyl)oxan-2-yl]oxymethyl]-3,4,5-tris(oxidanyl)oxan-2-yl]oxy-3,4,5-tris(oxidanyl)-6-[(2~{R},3~{S},4~{S},5~{S},6~{R})-3,4,5-tris(oxidanyl)-6-(undecanoyloxymethyl)oxan-2-yl]oxy-cyclohexyl]oxy-oxidanyl-phosphoryl]oxy-2-undecanoyloxy-propyl] (10~{R})-10-methyldodecanoate ChemComp-HEM: PROTOPORPHYRIN IX CONTAINING FE ChemComp-CDL: CARDIOLIPIN / phospholipidYM PDB-1iga: MODEL OF HUMAN IGA1 DETERMINED BY SOLUTION SCATTERING CURVE-FITTING AND HOMOLOGY MODELLING ChemComp-TRD: TRIDECANE ChemComp-3PE: 1,2-Distearoyl-sn-glycerophosphoethanolamine / phospholipidYM ChemComp-HEA: HEME-A ChemComp-CU: COPPER (II) ION ChemComp-CA: Unknown entry ChemComp-9XX: (2S)-1-(hexadecanoyloxy)propan-2-yl (10S)-10-methyloctadecanoate ChemComp-MG: Unknown entry ChemComp-PLM: PALMITIC ACID ChemComp-HOH: WATER
Source	mycolicibacterium smegmatis (bacteria)
Keywords	ELECTRON TRANSPORT / RESPIRATORY SUPERCOMPLEX / MEMBRANE PROTEIN / ACTINOBACTERIA