5KPD

Mouse pgp 34 linker deleted double EQ mutant

Summary for 5KPD

• Entry DOI: 10.2210/pdb5kpd/pdb
• Related: 5KO2 5KOY 5KPI 5KPJ
• Descriptor: Multidrug resistance protein 1A (1 entity in total)
• Functional Keywords: multidrug resistance, abc transporter, membrane protein, drug efflux, hydrolase
• Biological source: Mus musculus (Mouse)
• Cellular location: Cell membrane; Multi-pass membrane protein: P21447
• Total number of polymer chains: 2
• Total formula weight: 275586.66

Authors

Xia, D.,Esser, L.,Zhou, F. (deposition date: 2016-07-03, release date: 2016-11-30, Last modification date: 2023-10-04)

Primary citation

Esser, L.,Zhou, F.,Pluchino, K.M.,Shiloach, J.,Ma, J.,Tang, W.K.,Gutierrez, C.,Zhang, A.,Shukla, S.,Madigan, J.P.,Zhou, T.,Kwong, P.D.,Ambudkar, S.V.,Gottesman, M.M.,Xia, D.
Structures of the Multidrug Transporter P-glycoprotein Reveal Asymmetric ATP Binding and the Mechanism of Polyspecificity.
J. Biol. Chem., 292:446-461, 2017

PubMed Abstract: P-glycoprotein (P-gp) is a polyspecific ATP-dependent transporter linked to multidrug resistance in cancer; it plays important roles in determining the pharmacokinetics of many drugs. Understanding the structural basis of P-gp, substrate polyspecificity has been hampered by its intrinsic flexibility, which is facilitated by a 75-residue linker that connects the two halves of P-gp. Here we constructed a mutant murine P-gp with a shortened linker to facilitate structural determination. Despite dramatic reduction in rhodamine 123 and calcein-AM transport, the linker-shortened mutant P-gp possesses basal ATPase activity and binds ATP only in its N-terminal nucleotide-binding domain. Nine independently determined structures of wild type, the linker mutant, and a methylated P-gp at up to 3.3 Å resolution display significant movements of individual transmembrane domain helices, which correlated with the opening and closing motion of the two halves of P-gp. The open-and-close motion alters the surface topology of P-gp within the drug-binding pocket, providing a mechanistic explanation for the polyspecificity of P-gp in substrate interactions.

PubMed: 27864369
DOI: 10.1074/jbc.M116.755884

Experimental method

X-RAY DIFFRACTION (3.35 Å)