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Title | Structural Insights into Porphyrin Recognition by the Human ATP-Binding Cassette Transporter ABCB6. |
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Journal, issue, pages | Mol Cells, Vol. 45, Issue 8, Page 575-587, Year 2022 |
Publish date | Aug 31, 2022 |
Authors | Songwon Kim / Sang Soo Lee / Jun Gyou Park / Ji Won Kim / Seulgi Ju / Seung Hun Choi / Subin Kim / Na Jin Kim / Semi Hong / Jin Young Kang / Mi Sun Jin / |
PubMed Abstract | Human ABCB6 is an ATP-binding cassette transporter that regulates heme biosynthesis by translocating various porphyrins from the cytoplasm into the mitochondria. Here we report the cryo-electron ...Human ABCB6 is an ATP-binding cassette transporter that regulates heme biosynthesis by translocating various porphyrins from the cytoplasm into the mitochondria. Here we report the cryo-electron microscopy (cryo-EM) structures of human ABCB6 with its substrates, coproporphyrin III (CPIII) and hemin, at 3.5 and 3.7 Å resolution, respectively. Metalfree porphyrin CPIII binds to ABCB6 within the central cavity, where its propionic acids form hydrogen bonds with the highly conserved Y550. The resulting structure has an overall fold similar to the inward-facing apo structure, but the two nucleotide-binding domains (NBDs) are slightly closer to each other. In contrast, when ABCB6 binds a metal-centered porphyrin hemin in complex with two glutathione molecules (1 hemin: 2 glutathione), the two NBDs end up much closer together, aligning them to bind and hydrolyze ATP more efficiently. In our structures, a glycine-rich and highly flexible "bulge" loop on TM helix 7 undergoes significant conformational changes associated with substrate binding. Our findings suggest that ABCB6 utilizes at least two distinct mechanisms to fine-tune substrate specificity and transport efficiency. |
External links | Mol Cells / PubMed:35950458 / PubMed Central |
Methods | EM (single particle) |
Resolution | 3.4 - 3.6 Å |
Structure data | EMDB-30790, PDB-7dny: EMDB-30791, PDB-7dnz: |
Chemicals | ChemComp-Y01: ChemComp-HT9: ChemComp-GSH: ChemComp-HEM: |
Source |
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Keywords | MEMBRANE PROTEIN / ABCB6 / heme transporter |