PDBsum entry 4m2s

Hydrolase/hydrolase inhibitor

PDB id: 4m2s

Contents

Protein chains

1188 a.a.

Ligands

0JZ ×2

PDB id:

4m2s

Name:

Hydrolase/hydrolase inhibitor

Title:

Corrected structure of mouse p-glycoprotein bound to qz59-rrr

Structure:

Multidrug resistance protein 1a. Chain: a, b. Synonym: atp-binding cassette sub-family b member 1a, mdr1a, multidrug resistance protein 3, p-glycoprotein 3. Ec: 3.6.3.44

Source:

Mus musculus. Mouse. Organism_taxid: 10090

Resolution:

4.40Å R-factor: 0.234 R-free: 0.294

Authors:

J.Li,K.F.Jaimes,S.G.Aller

Key ref:

J.Li et al. (2014). Refined structures of mouse P-glycoprotein. Protein Sci, 23, 34-46. PubMed id: 24155053 DOI: 10.1002/pro.2387

Date:

05-Aug-13 Release date: 13-Nov-13

Protein chains

P21447  (MDR1A_MOUSE) -  ATP-dependent translocase ABCB1 from Mus musculus

Seq: 1276 a.a.

Struc: 1188 a.a.*

* PDB and UniProt seqs differ at 3 residue positions (black crosses)

Enzyme reactions

• Enzyme class 1: E.C.7.6.2.1 - P-type phospholipid transporter.
• Reaction: ATP + H2O + phospholipidSide 1 = ADP + phosphate + phospholipidSide 2
• Enzyme class 2: E.C.7.6.2.2 - ABC-type xenobiotic transporter.
• Reaction: ATP + H2O + xenobioticSide 1 = ADP + phosphate + xenobioticSide 2

Note, where more than one E.C. class is given (as above), each may correspond to a different protein domain or, in the case of polyprotein precursors, to a different mature protein.

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

reference

DOI no: 10.1002/pro.2387

Protein Sci 23:34-46 (2014)

PubMed id: 24155053

Refined structures of mouse P-glycoprotein.

J.Li, K.F.Jaimes, S.G.Aller.

ABSTRACT

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 Å 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 Å 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 three transmembrane (TM)4 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 Å 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 polyspecific substrate recognition.