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Conformational changes in the nucleotide-binding domains of P-glycoprotein induced by ATP hydrolysis. 2021

Sepehr Dehghani-Ghahnaviyeh, and Karan Kapoor, and Emad Tajkhorshid
Department of Biochemistry, NIH Center for Macromolecular Modeling and Bioinformatics, Center for Biophysics and Quantitative Biology, Beckman Institute for Advanced Science and Technology, University of Illinois at Urbana-Champaign, IL, USA.

P-glycoprotein (Pgp) is a member of the ABC transporter superfamily with high physiological importance. Pgp nucleotide-binding domains (NBDs) drive the transport cycle through ATP binding and hydrolysis. We use molecular dynamics simulations to investigate the ATP hydrolysis-induced conformational changes in NBDs. Five systems, including all possible ATP/ADP combinations in the NBDs and the APO system, are simulated. ATP/ADP exchange induces conformational changes mostly within the conserved signature motif of the NBDs, resulting in relative orientational changes in the NBDs. Nucleotide removal leads to additional orientational changes in the NBDs, allowing their dissociation. Furthermore, we capture putative hydrolysis-competent configurations in which the conserved glutamate in the Walker-B motif acts as a catalytic base capturing a water molecule likely initiating ATP hydrolysis.

UI MeSH Term Description Entries
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D006868 Hydrolysis The process of cleaving a chemical compound by the addition of a molecule of water.
D000255 Adenosine Triphosphate An adenine nucleotide containing three phosphate groups esterified to the sugar moiety. In addition to its crucial roles in metabolism adenosine triphosphate is a neurotransmitter. ATP,Adenosine Triphosphate, Calcium Salt,Adenosine Triphosphate, Chromium Salt,Adenosine Triphosphate, Magnesium Salt,Adenosine Triphosphate, Manganese Salt,Adenylpyrophosphate,CaATP,CrATP,Manganese Adenosine Triphosphate,MgATP,MnATP,ATP-MgCl2,Adenosine Triphosphate, Chromium Ammonium Salt,Adenosine Triphosphate, Magnesium Chloride,Atriphos,Chromium Adenosine Triphosphate,Cr(H2O)4 ATP,Magnesium Adenosine Triphosphate,Striadyne,ATP MgCl2
D056004 Molecular Dynamics Simulation A computer simulation developed to study the motion of molecules over a period of time. Molecular Dynamics Simulations,Molecular Dynamics,Dynamic, Molecular,Dynamics Simulation, Molecular,Dynamics Simulations, Molecular,Dynamics, Molecular,Molecular Dynamic,Simulation, Molecular Dynamics,Simulations, Molecular Dynamics
D018435 ATP Binding Cassette Transporter, Subfamily B A subfamily of transmembrane proteins from the superfamily of ATP-BINDING CASSETTE TRANSPORTERS that are closely related in sequence to ATP BINDING CASSETTE TRANSPORTER, SUBFAMILY B, MEMBER 1. When overexpressed, they function as ATP-dependent efflux pumps able to extrude lipophilic drugs (especially ANTINEOPLASTIC AGENTS) from cells, causing multidrug resistance (DRUG RESISTANCE, MULTIPLE). Although ATP BINDING CASSETTE TRANSPORTER, SUBFAMILY B share functional similarities to MULTIDRUG RESISTANCE-ASSOCIATED PROTEINS they are two distinct subclasses of ATP-BINDING CASSETTE TRANSPORTERS, and have little sequence homology. Multidrug Resistance Proteins,P-Glycoproteins,ATP Binding Cassette Transporter, Sub-Family B,ATP-Binding Cassette, Sub-Family B Proteins,ATP Binding Cassette Transporter, Sub Family B,ATP Binding Cassette, Sub Family B Proteins,P Glycoproteins
D020816 Amino Acid Motifs Three-dimensional protein structural elements that are composed of a combination of secondary structures. They include HELIX-LOOP-HELIX MOTIFS and ZINC FINGERS. Motifs are typically the most conserved regions of PROTEIN DOMAINS and are critical for domain function. However, the same motif may occur in proteins or enzymes with different functions. AA Motifs,Motifs, Amino Acid,Protein Motifs,Protein Structure, Supersecondary,Supersecondary Protein Structure,AA Motif,Amino Acid Motif,Motif, AA,Motif, Amino Acid,Motif, Protein,Motifs, AA,Motifs, Protein,Protein Motif,Protein Structures, Supersecondary,Supersecondary Protein Structures

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