6SAQ

wild-type NuoEF from Aquifex aeolicus bound to NADH-OH

PDB DOI: https://doi.org/10.2210/pdb6SAQ/pdb

Classification: ELECTRON TRANSPORT
Organism(s): Aquifex aeolicus VF5
Expression System: Escherichia coli
Mutation(s): No

Deposited: 2019-07-17 Released: 2020-07-22
Deposition Author(s): Gerhardt, S.
Funding Organization(s): German Research Foundation

Experimental Data Snapshot

Method: X-RAY DIFFRACTION
Resolution: 2.02 ?
R-Value Free: 0.181
R-Value Work: 0.159
R-Value Observed: 0.160

Starting Model: experimental
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wwPDB Validation 3D Report Full Report

Ligand Structure Quality Assessment

This is version 1.3 of the entry. See complete history.

Literature

Structural Basis for Inhibition of ROS-Producing Respiratory Complex I by NADH-OH.

Friedrich, T., Vranas, M., Wohlwend, D., Qiu, D., Gerhardt, S., Trncik, C., Pervaiz, M., Ritter, K., Steimle, S., Randazzo, A., Einsle, O., Gunther, S., Jessen, H.J., Kotlyar, A.

(2021) Angew Chem Int Ed Engl

PubMed: 34612584 Search on PubMedSearch on PubMed Central
DOI: https://doi.org/10.1002/anie.202112165
Primary Citation of Related Structures:
6SAQ

PubMed Abstract:
NADH:ubiquinone oxidoreductase, respiratory complex I, plays a central role in cellular energy metabolism. As a major source of reactive oxygen species (ROS) it affects ageing and mitochondrial dysfunction. The novel inhibitor NADH-OH specifically blocks NADH oxidation and ROS production by complex I in nanomolar concentrations. Attempts to elucidate its structure by NMR spectroscopy have failed. Here, by using X-ray crystallographic analysis, we report the structure of NADH-OH bound in the active site of a soluble fragment of complex I at 2.0?? resolution. We have identified key amino acid residues that are specific and essential for binding NADH-OH. Furthermore, the structure sheds light on the specificity of NADH-OH towards the unique Rossmann-fold of complex I and indicates a regulatory role in mitochondrial ROS generation. In addition, NADH-OH acts as a lead-structure for the synthesis of a novel class of ROS suppressors.

Organizational Affiliation

Institute of Biochemistry, University of Freiburg, 79104, Freiburg, Germany.

Macromolecule Content

Total Structure Weight: 138.2 kDa
Atom Count: 9,949
Modelled Residue Count: 1,146
Deposited Residue Count: 1,188
Unique protein chains: 2

Macromolecules

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(by identity cutoff) | 3D Structure

Entity ID: 1
Molecule	Chains	Sequence Length	Organism	Details	Image
NADH-quinone oxidoreductase subunit E	A, C	160	Aquifex aeolicus VF5	Mutation(s): 0 Gene Names: nuoE, aq_574 EC: 7.1.1
UniProt
Find proteins for O66842 (Aquifex aeolicus (strain VF5)) Explore O66842 Go to UniProtKB: O66842
Entity Groups
Sequence Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt Group	O66842
Sequence Annotations Expand
Reference Sequence

Find similar proteins by:

(by identity cutoff) | 3D Structure

Entity ID: 2
Molecule	Chains	Sequence Length	Organism	Details	Image
NADH-quinone oxidoreductase subunit F	B, D	434	Aquifex aeolicus VF5	Mutation(s): 0 Gene Names: nuoF, aq_573 EC: 7.1.1
UniProt
Find proteins for O66841 (Aquifex aeolicus (strain VF5)) Explore O66841 Go to UniProtKB: O66841
Entity Groups
Sequence Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt Group	O66841
Sequence Annotations Expand
Reference Sequence

Small Molecules

Ligands 5 Unique
ID	Chains	Name / Formula / InChI Key	2D Diagram	3D Interactions
L3W (Subject of Investigation/LOI) Query on L3W Download Ideal Coordinates CCD File SDF format, chain J [auth B] SDF format, chain Q [auth D] MOL2 format, chain J [auth B] MOL2 format, chain Q [auth D] mmCIF format, chain J [auth B] mmCIF format, chain Q [auth D]	J [auth B], Q [auth D]	[[(2~{R},3~{S},4~{R},5~{R})-5-(6-aminopurin-9-yl)-3,4-bis(oxidanyl)oxolan-2-yl]methoxy-oxidanyl-phosphoryl] [(2~{R},3~{S},4~{R},5~{R})-5-[[(1~{E},3~{Z})-5-azanyl-4-oxidanyl-5-oxidanylidene-penta-1,3-dienyl]-methanoyl-amino]-3,4-bis(oxidanyl)oxolan-2-yl]methyl hydrogen phosphate C₂₁ H₂₉ N₇ O₁₆ P₂ QSTZUQWNOOUKGF-OTTADCDWSA-N		Interactions Focus chain J [auth B] Focus chain Q [auth D] Interactions & Density Focus chain J [auth B] Focus chain Q [auth D]
FMN Query on FMN Download Ideal Coordinates CCD File SDF format, chain H [auth B] SDF format, chain O [auth D] MOL2 format, chain H [auth B] MOL2 format, chain O [auth D] mmCIF format, chain H [auth B] mmCIF format, chain O [auth D]	H [auth B], O [auth D]	FLAVIN MONONUCLEOTIDE C₁₇ H₂₁ N₄ O₉ P FVTCRASFADXXNN-SCRDCRAPSA-N		Interactions Focus chain H [auth B] Focus chain O [auth D] Interactions & Density Focus chain H [auth B] Focus chain O [auth D]
SF4 Query on SF4 Download Ideal Coordinates CCD File SDF format, chain I [auth B] SDF format, chain P [auth D] MOL2 format, chain I [auth B] MOL2 format, chain P [auth D] mmCIF format, chain I [auth B] mmCIF format, chain P [auth D]	I [auth B], P [auth D]	IRON/SULFUR CLUSTER Fe₄ S₄ LJBDFODJNLIPKO-UHFFFAOYSA-N		Interactions Focus chain I [auth B] Focus chain P [auth D] Interactions & Density Focus chain I [auth B] Focus chain P [auth D]
FES Query on FES Download Ideal Coordinates CCD File SDF format, chain E [auth A] SDF format, chain N [auth C] MOL2 format, chain E [auth A] MOL2 format, chain N [auth C] mmCIF format, chain E [auth A] mmCIF format, chain N [auth C]	E [auth A], N [auth C]	FE2/S2 (INORGANIC) CLUSTER Fe₂ S₂ NIXDOXVAJZFRNF-UHFFFAOYSA-N		Interactions Focus chain E [auth A] Focus chain N [auth C] Interactions & Density Focus chain E [auth A] Focus chain N [auth C]
GOL Query on GOL Download Ideal Coordinates CCD File SDF format, chain G [auth A] SDF format, chain K [auth B] SDF format, chain L [auth B] SDF format, chain M [auth B] SDF format, chain R [auth D] SDF format, chain S [auth D] SDF format, chain F [auth A] MOL2 format, chain G [auth A] MOL2 format, chain K [auth B] MOL2 format, chain L [auth B] MOL2 format, chain M [auth B] MOL2 format, chain R [auth D] MOL2 format, chain S [auth D] MOL2 format, chain F [auth A] mmCIF format, chain G [auth A] mmCIF format, chain K [auth B] mmCIF format, chain L [auth B] mmCIF format, chain M [auth B] mmCIF format, chain R [auth D] mmCIF format, chain S [auth D] mmCIF format, chain F [auth A]	F [auth A] G [auth A] K [auth B] L [auth B] M [auth B] F [auth A], G [auth A], K [auth B], L [auth B], M [auth B], R [auth D], S [auth D]	GLYCEROL C₃ H₈ O₃ PEDCQBHIVMGVHV-UHFFFAOYSA-N		Interactions Focus chain F [auth A] Focus chain G [auth A] Focus chain K [auth B] Focus chain L [auth B] Focus chain M [auth B] Focus chain R [auth D] Focus chain S [auth D] Interactions & Density Focus chain F [auth A] Focus chain G [auth A] Focus chain K [auth B] Focus chain L [auth B] Focus chain M [auth B] Focus chain R [auth D] Focus chain S [auth D]