Structural Basis of Substrate Recognition by the Multidrug Resistance Protein MRP1

Johnson, Z.L.; Chen, Jue

doi:10.1016/j.cell.2017.01.041

Cited by 327 publications

(548 citation statements)

References 90 publications

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“…80 a.a. long L0/Lasso motive with the TM10-11 helices. Although the Lasso motif is not a linker region in CFTR, because of the very high structural similarity with ABCC1/MRP1 L0 ( [29,30] and Supplementary Discussion) we suggest to call this segment in ABCC proteins as the L0/Lasso motif. This N-terminal region also contains amino acids with high solvation free energy values (Fig.…”

Section: Resultsmentioning

confidence: 99%

Molecular dynamics of the cryo-EM CFTR structure

Tordai

Leveles

Hegedüs

2017

Biochemical and Biophysical Research Communications

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Cystic fibrosis (CF), a lethal monogenic disease, is caused by mutant variants of the CF transmembrane conductance regulator (CFTR). Recent advances in single molecule cryo-EM methods enabled structural determination of full-length human and zebrafish CFTR, achieving an important milestone for CF drug development. To relate these structures to the gating cycle, we examined its dynamic features using molecular dynamics simulations. Our results show that the nucleotide binding domains (NBDs) in this bottom-open apo conformation exhibit motions related to dimerization and the bottom-closed apo CFTR model indicates opening of NBDs in contrast to transporters. These observations help in understanding the properties of CFTR chloride channel distinct from transporters and in proper interpretation of available structural information on this ABC protein.

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Section: Resultsmentioning

confidence: 99%

Molecular dynamics of the cryo-EM CFTR structure

Tordai

Leveles

Hegedüs

2017

Biochemical and Biophysical Research Communications

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“…Many members of this family are known to function as MDR efflux pumps, and thus here we refer to them as ABC MDR exporters. Based on substrate preference, these MDR exporters are further divided into two groups, namely (i) those recruiting lipophilic and cationic substrates (exemplified by Pgp of the ABC‐B subfamily) and (ii) those recruiting soluble organic acids (exemplified by MRP1 of the ABC‐C subfamily) . Since ABC transporters consume more energy in a functional cycle than secondary transporters, under physiological conditions ABC transporters are presumably used to transport substrates against a large kinetic barrier and/or a high uphill of thermodynamic potential.…”

Section: Structural Basis Of Functional Cycles Of Mdr Transportersmentioning

confidence: 99%

“…Similar to other MDR transporters, an ABC MDR exporter is composed of two (pseudo) symmetrical halves (Fig. ) . Each half of the transporter contains a 6‐helix TM domain (TMD) and a cytosolic nucleotide‐binding domain (NBD).…”

Section: Structural Basis Of Functional Cycles Of Mdr Transportersmentioning

confidence: 99%

“…Because of the electronegativity of its environment, D817 TM9 is presumably also protonated in the C In state. Upon loading of a lipophilic substrate, the micro‐environment of these key acidic residues will likely change, in addition to the substrate‐mediated partial closure of the bipartite structure of the transporter . For instance, interaction between R813 and the linker peptide will likely be disrupted, freeing the basic residue R813 to interact with D817 TM9 instead.…”

Section: Structural Basis Of Functional Cycles Of Mdr Transportersmentioning

confidence: 99%

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Thermodynamic secrets of multidrug resistance: A new take on transport mechanisms of secondary active antiporters

Zhang

Liu

et al. 2017

Protein Science

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Multidrug resistance (MDR) presents a growing challenge to global public health. Drug extrusion transporters play a critical part in MDR; thus, their mechanisms of substrate recognition are being studied in great detail. In this work, we review common structural features of key transporters involved in MDR. Based on our membrane potential-driving hypothesis, we propose a general energy-coupling mechanism for secondary-active antiporters. This putative mechanism provides a common framework for understanding poly-specificity of most-if not all-MDR transporters.

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“…Um dos mecanismos subjacentes da resistência a múltiplas drogas (RMD) é o efluxo ativo de drogas por proteínas transportadoras da superfamília ATP-Binding Cassette (ABC), ligadas à membrana celular (LUQMANI, 2008;KUNJACHAN et al, 2013;NIERO et al, 2014;WONG et al, 2014;CHEN, 2017 Os transportadores da família ABC são encontrados em todos os organismos, mas a glicoproteína-P humana ABC (Pgp/ABCB1), a proteína associada a resistência a múltiplas drogas-1 (MRP1/ABCC1) e a proteína de resistência ao câncer de mama (BCRP/ABCG2) estão entre os mais estudados devido ao seu papel no desenvolvimento de RMD no câncer (MEALEY et al, 2003SCHINKEL;JONKER, 2003;LESLIE;COLE, 2005;LUQMANI, 2008;MEALEY, 2012;KUNJACHAN et al, 2013;NIERO et al, 2014;WONG et al, 2014;ZANDVLIET;SCHRICKX, 2014 A expressão da Pgp já foi relatada em muitos tumores caninos (GINN, 1996;HIFUMI et al 2010;LEE, 2007, MIYOSHI et al, 2002.…”

Section: Transportadores Abcunclassified

<b>Estudo da expressão imunoistoquímica de marcadores de resistência a múltiplas drogas em cães com linfoma cutâneo</b>

Alves¹

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Among mechanisms of resistance are efflux of drugs from intracellular to extracellular through ABC family transporters such as P-glycoprotein, MRP (multple resistance protein) and BCRP (breast cancer resistance protein) and LRP (lung resistance protein), a vault protein responsible for nucleocytoplasmic transport. The aim of this study was to characterize immunophenotypically cutaneous lymphomas, measure cell proliferation using the Ki67 marker, the expression of resistance proteins Pglycoprotein, MRP, BCRP and LRP and to evaluate the relationship of these proteins with the survival of the animals. A retrospective study was performed with 21 cases of dogs with cutaneous lymphoma with histopathological diagnosis.Immunohistochemical was used to immunophenotyping of lymphomas by CD3 and CD20 markers, Ki67 cell proliferation, and P-glycoprotein, MRP, BCRP and LRP expression. Of the 21 animals, 38% had histopathological diagnosis of epitheliotropic lymphoma, 52% were non-epitheliotropic lymphomas, 5% of lymphoma cases had no definition and 5% were classified as round cell neoplasia. The predominant immunophenotype was CD3+CD20-(76%), 15% of the cases were CD3-CD20 + and 9% were CD3 + CD20 +. The median of cells labeled for Ki67 was 31%. Regarding the markers of resistance to multiple drugs, the median of the P-glycoprotein label was 40%, which 65% of LRP while for MRP and BCRP, 19% and 23%, respectively. Non-epitheliotropic cutaneous lymphomas were more frequent than epitheliotropic lymphomas and the predominant immunophenotype was T. The occurrence of CD3-CD20+ and CD3+CD20+ lymphocytes indicates the need for further studies and a wider panel of antibodies for subtyping these lymphomas. P-glycoprotein had higher expression in non-epitheliotropic lymphomas than in epitheliotropic lymphomas and there was no correlation between resistance proteins and survival time of the animals, suggesting that in addition to the biology of neoplasia other mechanisms of resistance to multiple drugs different from those studied may play a relevant role in the low response of cutaneous lymphoma to chemotherapy.

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Structural Basis of Substrate Recognition by the Multidrug Resistance Protein MRP1

Cited by 327 publications

References 90 publications

Molecular dynamics of the cryo-EM CFTR structure

Molecular dynamics of the cryo-EM CFTR structure

Thermodynamic secrets of multidrug resistance: A new take on transport mechanisms of secondary active antiporters

<b>Estudo da expressão imunoistoquímica de marcadores de resistência a múltiplas drogas em cães com linfoma cutâneo</b>

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