8K7C

Outward-facing structure of human ABCB6 W546A mutant (ADP/VO4-bound)

Summary for 8K7C

• Entry DOI: 10.2210/pdb8k7c/pdb
• Related: 7DNY 7DNZ
• EMDB information: 36938
• Descriptor: ATP-binding cassette sub-family B member 6, ADENOSINE-5'-DIPHOSPHATE, VANADATE ION, ... (4 entities in total)
• Functional Keywords: atp-binding cassette transporter, mitochondrial transporter, outward-facing state, adp/vo4-bound, abcb6, membrane protein, transport protein
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 132872.48

Authors

Jin, M.S.,Lee, S.S.,Park, J.G.,Jang, E.,Choi, S.H.,Kim, S.,Kim, J.W. (deposition date: 2023-07-26, release date: 2023-10-04)

Primary citation

Lee, S.S.,Park, J.G.,Jang, E.,Choi, S.H.,Kim, S.,Kim, J.W.,Jin, M.S.
W546 stacking disruption traps the human porphyrin transporter ABCB6 in an outward-facing transient state.
Commun Biol, 6:960-960, 2023

PubMed Abstract: Human ATP-binding cassette transporter subfamily B6 (ABCB6) is a mitochondrial ATP-driven pump that translocates porphyrins from the cytoplasm into mitochondria for heme biosynthesis. Within the transport pathway, a conserved aromatic residue W546 located in each monomer plays a pivotal role in stabilizing the occluded conformation via π-stacking interactions. Herein, we employed cryo-electron microscopy to investigate the structural consequences of a single W546A mutation in ABCB6, both in detergent micelles and nanodiscs. The results demonstrate that the W546A mutation alters the conformational dynamics of detergent-purified ABCB6, leading to entrapment of the transporter in an outward-facing transient state. However, in the nanodisc system, we observed a direct interaction between the transporter and a phospholipid molecule that compensates for the absence of the W546 residue, thereby facilitating the normal conformational transition of the transporter toward the occluded state following ATP hydrolysis. The findings also reveal that adoption of the outward-facing conformation causes charge repulsion between ABCB6 and the bound substrate, and rearrangement of key interacting residues at the substrate-binding site. Consequently, the affinity for the substrate is significantly reduced, facilitating its release from the transporter.

PubMed: 37735522
DOI: 10.1038/s42003-023-05339-3

Experimental method

ELECTRON MICROSCOPY (3.9 Å)