8jxu

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Cryo-EM structure of human ABC transporter ABCC2 under active turnover condition

Structural highlights

8jxu is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:Electron Microscopy, Resolution 3.55Å
Ligands:ADP, ATP, MG
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

MRP2_HUMAN Dubin-Johnson syndrome. The disease is caused by variants affecting the gene represented in this entry.

Function

MRP2_HUMAN ATP-dependent transporter of the ATP-binding cassette (ABC) family that binds and hydrolyzes ATP to enable active transport of various substrates including many drugs, toxicants and endogenous compound across cell membranes. Transports a wide variety of conjugated organic anions such as sulfate-, glucuronide- and glutathione (GSH)-conjugates of endo- and xenobiotics substrates (PubMed:10220572, PubMed:10421658, PubMed:11500505, PubMed:16332456). Mediates hepatobiliary excretion of mono- and bis-glucuronidated bilirubin molecules and therefore play an important role in bilirubin detoxification (PubMed:10421658). Mediates also hepatobiliary excretion of others glucuronide conjugates such as 17beta-estradiol 17-glucosiduronic acid and leukotriene C4 (PubMed:11500505). Transports sulfated bile salt such as taurolithocholate sulfate (PubMed:16332456). Transports various anticancer drugs, such as anthracycline, vinca alkaloid and methotrexate and HIV-drugs such as protease inhibitors (PubMed:10220572, PubMed:11500505, PubMed:12441801). Confers resistance to several anti-cancer drugs including cisplatin, doxorubicin, epirubicin, methotrexate, etoposide and vincristine (PubMed:10220572, PubMed:11500505).[1] [2] [3] [4] [5]

Publication Abstract from PubMed

Bilirubin is mainly generated from the breakdown of heme when red blood cells reach the end of their lifespan. Accumulation of bilirubin in human body usually leads to various disorders, including jaundice and liver disease. Bilirubin is conjugated in hepatocytes and excreted to bile duct via the ATP-binding cassette transporter ABCC2, dysfunction of which would lead to Dubin-Johnson syndrome. Here we determine the structures of ABCC2 in the apo, substrate-bound and ATP/ADP-bound forms using the cryo-electron microscopy, exhibiting a full transporter with a regulatory (R) domain inserted between the two half modules. Combined with substrate-stimulated ATPase and transport activity assays, structural analysis enables us to figure out transport cycle of ABCC2 with the R domain adopting various conformations. At the rest state, the R domain binding to the translocation cavity functions as an affinity filter that allows the substrates of high affinity to be transported in priority. Upon substrate binding, the R domain is expelled from the cavity and docks to the lateral of transmembrane domain following ATP hydrolysis. Our findings provide structural insights into a transport mechanism of ABC transporters finely tuned by the R domain.

Transport mechanism of human bilirubin transporter ABCC2 tuned by the inter-module regulatory domain.,Mao YX, Chen ZP, Wang L, Wang J, Zhou CZ, Hou WT, Chen Y Nat Commun. 2024 Feb 5;15(1):1061. doi: 10.1038/s41467-024-45337-5. PMID:38316776[6]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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Citations
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Structural basis for autoinhibition by the dephosphorylated regulatory domain of Ycf1.
Khandelwal et al. (2024)
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References

  1. ↑ Cui Y, König J, Buchholz JK, Spring H, Leier I, Keppler D. Drug resistance and ATP-dependent conjugate transport mediated by the apical multidrug resistance protein, MRP2, permanently expressed in human and canine cells. Mol Pharmacol. 1999 May;55(5):929-37 PMID:10220572
  2. ↑ Kamisako T, Leier I, Cui Y, König J, Buchholz U, Hummel-Eisenbeiss J, Keppler D. Transport of monoglucuronosyl and bisglucuronosyl bilirubin by recombinant human and rat multidrug resistance protein 2. Hepatology. 1999 Aug;30(2):485-90. PMID:10421658 doi:10.1002/hep.510300220
  3. ↑ Ito K, Oleschuk CJ, Westlake C, Vasa MZ, Deeley RG, Cole SP. Mutation of Trp1254 in the multispecific organic anion transporter, multidrug resistance protein 2 (MRP2) (ABCC2), alters substrate specificity and results in loss of methotrexate transport activity. J Biol Chem. 2001 Oct 12;276(41):38108-14. PMID:11500505 doi:10.1074/jbc.M105160200
  4. ↑ Huisman MT, Smit JW, Crommentuyn KM, Zelcer N, Wiltshire HR, Beijnen JH, Schinkel AH. Multidrug resistance protein 2 (MRP2) transports HIV protease inhibitors, and transport can be enhanced by other drugs. AIDS. 2002 Nov 22;16(17):2295-301. PMID:12441801 doi:10.1097/00002030-200211220-00009
  5. ↑ Hayashi H, Takada T, Suzuki H, Onuki R, Hofmann AF, Sugiyama Y. Transport by vesicles of glycine- and taurine-conjugated bile salts and taurolithocholate 3-sulfate: a comparison of human BSEP with rat Bsep. Biochim Biophys Acta. 2005 Dec 30;1738(1-3):54-62. doi:, 10.1016/j.bbalip.2005.10.006. Epub 2005 Nov 15. PMID:16332456 doi:http://dx.doi.org/10.1016/j.bbalip.2005.10.006
  6. ↑ Mao YX, Chen ZP, Wang L, Wang J, Zhou CZ, Hou WT, Chen Y. Transport mechanism of human bilirubin transporter ABCC2 tuned by the inter-module regulatory domain. Nat Commun. 2024 Feb 5;15(1):1061. PMID:38316776 doi:10.1038/s41467-024-45337-5

Contents


PDB ID 8jxu

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