alexa Nucleotide-free Crystal Structure of Nucleotide-binding
ISSN: 2167-0501

Biochemistry & Pharmacology: Open Access
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Research Article

Nucleotide-free Crystal Structure of Nucleotide-binding Domain 1 from Human ABCC1 Supports a ‘General-Base Catalysis’ Mechanism for ATP Hydrolysis

Vincent Chaptal1*, Sandrine Magnard1, Virginie Gueguen-Chaignon2, Pierre Falson1, Attilio Di Pietro1 and Hélène Baubichon-Cortay1
1Mechanisms and Modulation of Drug Resistance Team, Equipe Labellisée Ligue 2014, BMSSI UMR5086, CNRS-University Lyon-1, IBCP, 7 Passage du Vercors, 69367 Lyon, France
2Protein Science Facility, Institute of Biology and Chemistry of Proteins, SFR Biosciences/FR3302, 7 Passage du Vercors, 69367 Lyon, France
Corresponding Author : Vincent Chaptal
Mechanisms and Modulation of Drug Resistance Team
Institute of Biology and Chemistry of Proteins
BMSSI UMR 5086 CNRS/University of Lyon 1
7 Passage du Vercors, 69367 Lyon, France
E-mail: [email protected]
Received: September 24, 2014; Accepted: October 21, 2014; Published October 27, 2014
Citation: Chaptal V, Magnard S, Gueguen-Chaignon V, Falson P, Di Pietro A, et al. (2014) Nucleotide-free Crystal Structure of Nucleotide-binding Domain 1 from Human ABCC1 Supports a ‘General-Base Catalysis’ Mechanism for ATP Hydrolysis. Biochem Pharmacol 3:150. doi:10.4172/2167-0501.1000150
Copyright: © 2014 Chaptal V, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
 

Abstract

ATP-binding cassette (ABC) transporters are molecular motors that transport substrates through biological membranes, using the energy of ATP binding and hydrolysis to foster a series of conformational changes that follow the alternating access mechanism principles. While this general scheme of substrate transport is well accepted, details about the ATP hydrolysis mechanism itself are still a matter of debate. Decades of biochemical and structural studies have identified well-conserved key residues involved in the enzymatic reaction, but their actual role, or order in the hydrolytic process, differ according to the mechanism involved. Here, we investigate the fundamental mechanisms of ATP hydrolysis, by reporting the nucleotide-free structure of the N-terminal nucleotide-Binding Domain (NBD1) of human Multidrug Resistance Protein 1 (MRP1/ABCC1), a transporter of chemotherapeutic drugs. Comparison with the nucleotide-bound structure clearly identified movements of H827 associated with nucleotide binding and release of the active site. These results, put in the context of other structural information and mutational studies of ABC transporters, support the general-base catalysis mechanism for ATP hydrolysis for ABCC1.

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