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-Structure paper
タイトル | Structural and mechanistic basis of substrate transport by the multidrug transporter MRP4. |
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ジャーナル・号・ページ | Structure, Vol. 31, Issue 11, Page 1407-11418.e6, Year 2023 |
掲載日 | 2023年11月2日 |
![]() | Magnus Bloch / Isha Raj / Tillmann Pape / Nicholas M I Taylor / ![]() |
PubMed 要旨 | Multidrug resistance-associated protein 4 (MRP4) is an ATP-binding cassette (ABC) transporter expressed at multiple tissue barriers where it actively extrudes a wide variety of drug compounds. ...Multidrug resistance-associated protein 4 (MRP4) is an ATP-binding cassette (ABC) transporter expressed at multiple tissue barriers where it actively extrudes a wide variety of drug compounds. Overexpression of MRP4 provides resistance to clinically used antineoplastic agents, making it a highly attractive therapeutic target for countering multidrug resistance. Here, we report cryo-EM structures of multiple physiologically relevant states of lipid bilayer-embedded human MRP4, including complexes between MRP4 and two widely used chemotherapeutic agents and a complex between MRP4 and its native substrate. The structures display clear similarities and distinct differences in the coordination of these chemically diverse substrates and, in combination with functional and mutational analysis, reveal molecular details of the transport mechanism. Our study provides key insights into the unusually broad substrate specificity of MRP4 and constitutes an important contribution toward a general understanding of multidrug transporters. |
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手法 | EM (単粒子) |
解像度 | 3.0 - 5.5 Å |
構造データ | EMDB-16088, PDB-8bjf: EMDB-16292: Cryo-EM structure of nanodisc-reconstituted human MRP4 withE1202Q mutation (outward-facing occluded conformation) EMDB-16293, PDB-8bwp: EMDB-16294, PDB-8bwq: EMDB-16295, PDB-8bwr: ![]() EMDB-16296: Cryo-EM structure of native nanodisc-reconstituted wildtype human MRP4 (inward-facing conformation) - no nucleotides/substrates added ![]() EMDB-16297: Cryo-EM structure of minimal nanodisc-reconstituted wildtype human MRP4 (inward-facing conformation) - no nucleotides/substrates added |
化合物 | ![]() ChemComp-CLR: ![]() ChemComp-Y01: ![]() ChemComp-ATP: ![]() ChemComp-MG: ![]() ChemComp-MTX: ![]() ChemComp-TTC: ![]() ChemComp-P2E: |
由来 |
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![]() | TRANSLOCASE / ABC transporter / ABCC4 / MRP4 / Topotecan bound / PGE2 bound ABC transporter |