PDBsum entry 2gmh

Oxidoreductase

PDB id: 2gmh

Contents

Protein chains

581 a.a.

Ligands

BHG ×3

SF4 ×2

FAD ×2

UQ5 ×2

EDO ×10

Metals

_NA

Waters ×369

References listed in PDB file

Key reference

Title

Structure of electron transfer flavoprotein-Ubiquinone oxidoreductase and electron transfer to the mitochondrial ubiquinone pool.

Authors

J.Zhang, F.E.Frerman, J.J.Kim.

Ref.

Proc Natl Acad Sci U S A, 2006, 103, 16212-16217. [DOI no: 10.1073/pnas.0604567103]

PubMed id

17050691

Abstract

Electron transfer flavoprotein-ubiquinone oxidoreductase (ETF-QO) is a 4Fe4S flavoprotein located in the inner mitochondrial membrane. It catalyzes ubiquinone (UQ) reduction by ETF, linking oxidation of fatty acids and some amino acids to the mitochondrial respiratory chain. Deficiencies in ETF or ETF-QO result in multiple acyl-CoA dehydrogenase deficiency, a human metabolic disease. Crystal structures of ETF-QO with and without bound UQ were determined, and they are essentially identical. The molecule forms a single structural domain. Three functional regions bind FAD, the 4Fe4S cluster, and UQ and are closely packed and share structural elements, resulting in no discrete structural domains. The UQ-binding pocket consists mainly of hydrophobic residues, and UQ binding differs from that of other UQ-binding proteins. ETF-QO is a monotopic integral membrane protein. The putative membrane-binding surface contains an alpha-helix and a beta-hairpin, forming a hydrophobic plateau. The UQ-flavin distance (8.5 A) is shorter than the UQ-cluster distance (18.8 A), and the very similar redox potentials of FAD and the cluster strongly suggest that the flavin, not the cluster, transfers electrons to UQ. Two possible electron transfer paths can be envisioned. First, electrons from the ETF flavin semiquinone may enter the ETF-QO flavin one by one, followed by rapid equilibration with the cluster. Alternatively, electrons may enter via the cluster, followed by equilibration between centers. In both cases, when ETF-QO is reduced to a two-electron reduced state (one electron at each redox center), the enzyme is primed to reduce UQ to ubiquinol via FAD.

Figure 1.
Fig. 1. Ribbon diagram of ETF-QO. The structure comprises three domains: FAD domain (blue), 4Fe4S cluster domain (red), and UQ-binding domain (green). Three redox centers are shown in sticks: FAD (golden yellow), 4Fe4S (magenta), and UQ (dark red). -Helices and -strands are numbered sequentially from the N terminus to the C terminus. The putative membrane-associated surface regions are shown in cyan. Mitochondrial membrane is depicted as blue shaded area.

Figure 4.
Fig. 4. Electrostatic potential surface of ETF-QO viewed from the membrane side. Entrance to the UQ-binding site (dashed circle) and the UQ polyisoprene tail (green sticks) are shown. The surrounding positively charged groups (blue patches) probably are involved in interacting with the negatively charged membrane phospholipid heads. The size of the entrance (dashed circle) is 10 Å x 6 Å and that of the hydrophobic plateau (blue parallelogram) is 24 Å x 30 Å. Color codes are blue for positive (+8 kT), white for neutral, and red for negative (–8 kT).