4m2s

Corrected Structure of Mouse P-glycoprotein bound to QZ59-RRR

spinqualitylabelsall models 4m2s, resolution 4.40Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4m2s is a 2 chain structure with sequence from Mus musculus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: 0JZ Related: 4m1m, 4m2t, 3g5u, 3g60, 3g61 Activity: Xenobiotic-transporting ATPase, with EC number 3.6.3.44 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function [MDR1A_MOUSE] Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells. Publication Abstract from PubMed The recently determined C. elegans P-glycoprotein (Pgp) structure revealed significant deviations compared to the original mouse Pgp structure, which suggested possible misinterpretations in the latter model. To address this concern, we generated an experimental electron density map from single-wavelength anomalous dispersion phasing of an original mouse Pgp dataset to 3.8 A resolution. The map exhibited significantly more detail compared to the original MAD map and revealed several regions of the structure that required de novo model building. The improved drug-free structure was refined to 3.8 A resolution with a 9.4% and 8.1% decrease in Rwork and Rfree , respectively (Rwork =21.2%, Rfree =26.6%) and a significant improvement in protein geometry. The improved mouse Pgp model contains ~ 95% of residues in the favorable Ramachandran region compared to only 57% for the original model. The registry of six transmembrane helices was corrected, revealing amino acid residues involved in drug binding that were previously unrecognized. Registry shifts (rotations and translations) for TM4 and TM5 and the addition of three N-terminal residues were necessary, and were validated with new mercury labeling and anomalous fourier density. The corrected position of TM4, which forms the frame of a portal for drug entry, had backbone atoms shifted > 6 A from their original positions. The drug translocation pathway of mouse Pgp is 96% identical to human Pgp and is enriched in aromatic residues that likely play a collective role in allowing a high degree of polyspecificity in substrate recognition. Refined structures of mouse P-Glycoprotein.,Li J, Jaimes KF, Aller SG Protein Sci. 2013 Oct 24. doi: 10.1002/pro.2387. PMID:24155053 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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