PDBsum entry 4xwk

Hydrolase

PDB id: 4xwk

Contents

Protein chain

1182 a.a.

Ligands

4C8

PDB id:

4xwk

Name:

Hydrolase

Title:

P-glycoprotein co-crystallized with bde-100

Structure:

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

Source:

Mus musculus. Mouse. Organism_taxid: 10090. Gene: abcb1a, abcb4, mdr1a, mdr3, pgy-3, pgy3. Expressed in: pichia pastoris. Expression_system_taxid: 4922.

Resolution:

3.50Å R-factor: 0.264 R-free: 0.282

Authors:

A.P.Mcgrath,S.D.Rees,G.Chang

Key ref:

S.C.Nicklisch et al. (2016). Global marine pollutants inhibit P-glycoprotein: Environmental levels, inhibitory effects, and cocrystal structure. Sci Adv, 2, e1600001. PubMed id: 27152359 DOI: 10.1126/sciadv.1600001

Date:

29-Jan-15 Release date: 27-Apr-16

Protein chain

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

Seq: 1276 a.a.

Struc: 1182 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: 10.1126/sciadv.1600001

Sci Adv 2:e1600001 (2016)

PubMed id: 27152359

Global marine pollutants inhibit P-glycoprotein: Environmental levels, inhibitory effects, and cocrystal structure.

S.C.Nicklisch, S.D.Rees, A.P.McGrath, T.Gökirmak, L.T.Bonito, L.M.Vermeer, C.Cregger, G.Loewen, S.Sandin, G.Chang, A.Hamdoun.

ABSTRACT

The world's oceans are a global reservoir of persistent organic pollutants to which humans and other animals are exposed. Although it is well known that these pollutants are potentially hazardous to human and environmental health, their impacts remain incompletely understood. We examined how persistent organic pollutants interact with the drug efflux transporter P-glycoprotein (P-gp), an evolutionarily conserved defense protein that is essential for protection against environmental toxicants. We identified specific congeners of organochlorine pesticides, polychlorinated biphenyls, and polybrominated diphenyl ethers that inhibit mouse and human P-gp, and determined their environmental levels in yellowfin tuna from the Gulf of Mexico. In addition, we solved the cocrystal structure of P-gp bound to one of these inhibitory pollutants, PBDE (polybrominated diphenyl ether)-100, providing the first view of pollutant binding to a drug transporter. The results demonstrate the potential for specific binding and inhibition of mammalian P-gp by ubiquitous congeners of persistent organic pollutants present in fish and other foods, and argue for further consideration of transporter inhibition in the assessment of the risk of exposure to these chemicals.