|Entry||Database: EMDB / ID: 4283|
|Title||Apo form of UIC2 Fab complex of human-mouse chimeric ABCB1 (ABCB1HM) - Map 2 (kinked TM4 and TM10)|
|Sample||Apo Human-mouse chimeric ABCB1 (ABCB1HM) complex with UIC2 fab|
|Source||Homo sapiens (human) / Mus musculus (house mouse)|
|Method||single particle reconstruction / cryo EM / 4.47 Å resolution|
|Authors||Alam A / Locher KP|
|Citation||Journal: Proc. Natl. Acad. Sci. U.S.A. / Year: 2018|
Title: Structure of a zosuquidar and UIC2-bound human-mouse chimeric ABCB1.
Authors: Amer Alam / Raphael Küng / Julia Kowal / Robert A McLeod / Nina Tremp / Eugenia V Broude / Igor B Roninson / Henning Stahlberg / Kaspar P Locher
Abstract: The multidrug transporter ABCB1 (P-glycoprotein) is an ATP-binding cassette transporter that has a key role in protecting tissues from toxic insult and contributes to multidrug extrusion from cancer ...The multidrug transporter ABCB1 (P-glycoprotein) is an ATP-binding cassette transporter that has a key role in protecting tissues from toxic insult and contributes to multidrug extrusion from cancer cells. Here, we report the near-atomic resolution cryo-EM structure of nucleotide-free ABCB1 trapped by an engineered disulfide cross-link between the nucleotide-binding domains (NBDs) and bound to the antigen-binding fragment of the human-specific inhibitory antibody UIC2 and to the third-generation ABCB1 inhibitor zosuquidar. Our structure reveals the transporter in an occluded conformation with a central, enclosed, inhibitor-binding pocket lined by residues from all transmembrane (TM) helices of ABCB1. The pocket spans almost the entire width of the lipid membrane and is occupied exclusively by two closely interacting zosuquidar molecules. The external, conformational epitope facilitating UIC2 binding is also visualized, providing a basis for its inhibition of substrate efflux. Additional cryo-EM structures suggest concerted movement of TM helices from both halves of the transporters associated with closing the NBD gap, as well as zosuquidar binding. Our results define distinct recognition interfaces of ABCB1 inhibitory agents, which may be exploited for therapeutic purposes.
|Date||Deposition: Feb 2, 2018 / Header (metadata) release: Feb 14, 2018 / Map release: Feb 21, 2018 / Last update: Mar 7, 2018|
|Structure viewer||EM map: |
Downloads & links
|File||emd_4283.map.gz (map file in CCP4 format, 32001 KB)|
|Projections & slices|
Images are generated by Spider.
|Voxel size||X=Y=Z: 1.387 Å|
CCP4 map header:
-Entire Apo Human-mouse chimeric ABCB1 (ABCB1HM) complex with UIC2 fab
|Entire||Name: Apo Human-mouse chimeric ABCB1 (ABCB1HM) complex with UIC2 fab|
Number of components: 3
-Component #1: protein, Apo Human-mouse chimeric ABCB1 (ABCB1HM) complex with UI...
|Protein||Name: Apo Human-mouse chimeric ABCB1 (ABCB1HM) complex with UIC2 fab|
Recombinant expression: No
|Mass||Theoretical: 195 kDa|
-Component #2: protein, Apo Human-mouse chimeric ABCB1 (ABCB1HM)
|Protein||Name: Apo Human-mouse chimeric ABCB1 (ABCB1HM) / Recombinant expression: No|
|Mass||Theoretical: 142 kDa|
|Source||Species: Homo sapiens (human)|
|Source (engineered)||Expression System: Homo sapiens (human)|
-Component #3: protein, UIC2 fab
|Protein||Name: UIC2 fab / Recombinant expression: No|
|Mass||Theoretical: 48.7 kDa|
|Source||Species: Mus musculus (house mouse)|
|Source (engineered)||Expression System: Mus musculus (house mouse)|
|Specimen||Specimen state: particle / Method: cryo EM|
|Sample solution||pH: 7.5|
|Vitrification||Cryogen name: ETHANE|
-Electron microscopy imaging
Model: Titan Krios / Image courtesy: FEI Company
|Imaging||Microscope: FEI TITAN KRIOS|
|Electron gun||Electron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Electron dose: 0.9 e/Å2 / Illumination mode: FLOOD BEAM|
|Lens||Imaging mode: BRIGHT FIELD|
|Specimen Holder||Model: OTHER|
|Camera||Detector: GATAN K2 SUMMIT (4k x 4k)|
|Processing||Method: single particle reconstruction / Number of projections: 153652|
|3D reconstruction||Resolution: 4.47 Å / Resolution method: FSC 0.143 CUT-OFF|
-Jul 12, 2017. Major update of PDB
Major update of PDB
- wwPDB released updated PDB data conforming to the new PDBx/mmCIF dictionary. This is a major update changing the version number from 4 to 5, and with Remediation, in which all the entries are updated. See below links for details.
- In this update, many items about electron microscopy experimental information are reorganized (e.g. em_software). Now, EM Navigator and Yorodumi are based on the updated data.
-Jun 16, 2017. Omokage search with filter
Omokage search with filter
- Result of Omokage search can be filtered by keywords and the database types
Related info.: Omokage search
+Sep 15, 2016. EM Navigator & Yorodumi renewed
EM Navigator & Yorodumi renewed
- New versions of EM Navigator and Yorodumi started
Related info.: Changes in new EM Navigator and Yorodumi
+Aug 31, 2016. New EM Navigator & Yorodumi
New EM Navigator & Yorodumi
- In 15th Sep 2016, the development versions of EM Navigator and Yorodumi will replace the official versions.
- Current version will continue as 'legacy version' for some time.
Related info.: Changes in new EM Navigator and Yorodumi / EM Navigator / Yorodumi
+Apr 13, 2016. Omokage search got faster
Omokage search got faster
- The computation time became ~1/2 compared to the previous version by re-optimization of data accession
- Enjoy "shape similarity" of biomolecules, more!
Related info.: Omokage search
Thousand views of thousand structures
- Yorodumi is a browser for structure data from EMDB, PDB, SASBDB, etc.
- This page is also the successor to EM Navigator detail page, and also detail information page/front-end page for Omokage search.
Related info.: EMDB / PDB / SASBDB / Comparison of 3 databanks / Yorodumi Search / Aug 31, 2016. New EM Navigator & Yorodumi / Yorodumi Papers / Jmol/JSmol / Function and homology information / Changes in new EM Navigator and Yorodumi