PDBsum entry 4q9h

Hydrolase

PDB id: 4q9h

Contents

Protein chain

1182 a.a.

PDB id:

4q9h

Name:

Hydrolase

Title:

P-glycoprotein at 3.4 a resolution

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

Source:

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

Resolution:

3.40Å R-factor: 0.262 R-free: 0.291

Authors:

A.P.Mcgrath,P.Szewczyk,G.Chang

Key ref:

P.Szewczyk et al. (2015). Snapshots of ligand entry, malleable binding and induced helical movement in P-glycoprotein. Acta Crystallogr D Biol Crystallogr, 71, 732-741. PubMed id: 25760620 DOI: 10.1107/S1399004715000978

Date:

01-May-14 Release date: 04-Mar-15

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: 10.1107/S1399004715000978

Acta Crystallogr D Biol Crystallogr 71:732-741 (2015)

PubMed id: 25760620

Snapshots of ligand entry, malleable binding and induced helical movement in P-glycoprotein.

P.Szewczyk, H.Tao, A.P.McGrath, M.Villaluz, S.D.Rees, S.C.Lee, R.Doshi, I.L.Urbatsch, Q.Zhang, G.Chang.

ABSTRACT

P-glycoprotein (P-gp) is a transporter of great clinical and pharmacological significance. Several structural studies of P-gp and its homologs have provided insights into its transport cycle, but questions remain regarding how P-gp recognizes diverse substrates and how substrate binding is coupled to ATP hydrolysis. Here, four new P-gp co-crystal structures with a series of rationally designed ligands are presented. It is observed that the binding of certain ligands, including an ATP-hydrolysis stimulator, produces a large conformational change in the fourth transmembrane helix, which is positioned to potentially transmit a signal to the nucleotide-binding domains. A new ligand-binding site on the surface of P-gp facing the inner leaflet of the membrane is also described, providing vital insights regarding the entry mechanism of hydrophobic drugs and lipids into P-gp. These results represent significant advances in the understanding of how P-gp and related transporters bind and export a plethora of metabolites, antibiotics and clinically approved and pipeline drugs.