7dny | pdb_00007dny
Cryo-EM structure of the human ABCB6 (coproporphyrin III-bound)
Structural highlights
DiseaseABCB6_HUMAN Ocular coloboma;Dyschromatosis universalis;Colobomatous microphthalmia. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry. ABCB6 mutations are involved in familial pseudohyperkalemia, a dominantly inherited condition characterized by increased serum potassium levels, measured in whole-blood specimens stored at or below room temperature. This condition is not accompanied by clinical symptoms or biological signs except for borderline abnormalities of red cell shape (PubMed:23180570).[1] FunctionABCB6_HUMAN Binds heme and porphyrins and functions in their ATP-dependent uptake into the mitochondria. Plays a crucial role in heme synthesis.[2] [3] Publication Abstract from PubMedHuman 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 A 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. Structural Insights into Porphyrin Recognition by the Human ATP-Binding Cassette Transporter ABCB6.,Kim S, Lee SS, Park JG, Kim JW, Ju S, Choi SH, Kim S, Kim NJ, Hong S, Kang JY, Jin MS Mol Cells. 2022 Aug 31;45(8):575-587. doi: 10.14348/molcells.2022.0040. Epub 2022 , Jul 28. PMID:35950458[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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