Towards understanding promiscuity in multidrug efflux pumps

Wong, Kelvin; Ma, Jerome; Rothnie, Alice; Biggin, Philip C.; Kerr, Ian D.

doi:10.1016/j.tibs.2013.11.002

Cited by 114 publications

(97 citation statements)

References 64 publications

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“…The multidrug resistance of cancers and bacterial infections is an increasing and troublesome problem nowadays, due to the appearance of resistant cancers and resistant bacterial strains [27][28] . It has been observed that one of the most common mechanisms of cancer MDR is the over-expression of the efflux pumps 29 , which are membrane proteins that can recognise and extrude out of the cells toxic agents such as the anticancer drugs 29,30 .…”

mentioning

confidence: 99%

Selenoesters and selenoanhydrides as novel multidrug resistance reversing agents: A confirmation study in a colon cancer MDR cell line

Gajdács

Spengler

Sanmartín

et al. 2017

Bioorganic & Medicinal Chemistry Letters

103

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mentioning

confidence: 99%

Selenoesters and selenoanhydrides as novel multidrug resistance reversing agents: A confirmation study in a colon cancer MDR cell line

Gajdács

Spengler

Sanmartín

et al. 2017

Bioorganic & Medicinal Chemistry Letters

103

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“…Organisms acquire this ability through evolutionary force (1). Due to the development of scientific knowledge, more and more medical drugs are being developed and applied.…”

mentioning

confidence: 99%

Identification of the High-affinity Substrate-binding Site of the Multidrug and Toxic Compound Extrusion (MATE) Family Transporter from Pseudomonas stutzeri

Nie

Grell

Malviya

et al. 2016

Journal of Biological Chemistry

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Multidrug and toxic compound extrusion (MATE) transportThe ability of all living organisms to protect themselves against toxic substances is essential for their survival. Organisms acquire this ability through evolutionary force (1). Due to the development of scientific knowledge, more and more medical drugs are being developed and applied. As a consequence, general defense mechanisms to resist antibiotics, drugs, and other toxic compounds have been evolved in bacteria (2). Being one of those defense mechanisms, the active extrusion of the toxic compounds from the cells plays an important role (3). In bacteria, the extrusion is often carried out by multidrug transporters, which are integral membrane proteins. They are classified into five distinct families: ATP-binding cassette, multidrug and toxic compound extrusion (MATE), 4 major facilitator superfamily, resistance nodulation division, and small multidrug resistance transporters (4).In 1999, the MATE family proteins were first recognized as a new group of the multidrug transporters, existing in all three domains of life (5). Most members of this family consist of a single chain of 450 -550 amino acid residues and exhibit 12 putative transmembrane helices (TMHs). Up to now, about 900 proteins have been annotated as MATE transporters on the basis of amino acid sequence similarities. Moreover, a subclassification of the MATE family has been suggested, NorM-, DinF-(DNA damage-inducible protein F), and eukaryotic subfamily (4, 6, 7). Various compounds can be recognized by NorM proteins, including dyes, fluoroquinolones, and aminoglycosides (7). As secondary active transporters, MATE proteins utilize transmembrane Na ϩ or H ϩ electrochemical gradients to extrude toxic compounds.So far atomic structures of four MATE transporters have been reported in their putative outward-facing states, in both drug-bound and/or drug-free states. NorM_VC from Vibrio cholerae and NorM_NG from Neisseria gonorrhoeae, are both Na ϩ driven, whereas PfMATE from Pyrococcus furiosus and DinF-BH from Bacillus halodurans are published to be H ϩ -dependent antiporters (8 -11). All these four proteins contain 12 TMHs with intracellular N and C termini, and possess a hydrophobic internal cavity, formed by two symmetric bundles with 6 TMHs each. The two bundles are linked by a cytoplasmic loop between the 6th and 7th TMH. All MATE proteins share about 40% sequence similarity, and they employ the same rockerswitch mechanism for substrate extrusion (12). In addition, the crystal structures have also revealed different locations of cationand substrate-binding sites, suggesting a mechanistic diversity among MATE transporters. In the structure of drug-bound NorM_NG, the binding site is located close to the membraneperiplasm interface, whereas in the structure of PfMATE, the

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“…Tačan broj vezivnih mesta na transporteru nije jasno definisan: u različitim studijama sugerisano je postojanje od 2 do 7 razlilčitih vezivnih mesta, koja međusobno stupaju u složene alosterne interakcije [32][33][34][35]. Po savremenim tumačenjima, Pgp ne poseduje jasno definisana, prostorno razdvojena vezivna mesta, već jednu prilagodljivu vezivnu regiju sa oblastima za koje pojedini supstrati pokazuju izražen afinitet [36,37]. Novije biohemijske studije, kao i simulacije molekularne dinamike, ukazuju da u supstratnoj polispecifičnosti Pgp-a ključnu ulogu ima i izražena fleksibilnost transportera [38].…”

Section: Supstratna Polispecifičnost Pgp-a Kao Izazov U Uspostavljanjunclassified

Computational models for predicting drug transport mediated by P-glycoprotein

Erić¹,

Kalinić²

2015

Arh farmaciju

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Kratak sadržajP-glikoprotein (Pgp) je transmembranski transporter koji, transportujući strukturno raznovrsne lekove iz unutrašnjosti ćelije u ekstracelularnu sredinu, može uticati na resorpciju, distribuciju i efikasnost većeg broja lekova. Prekomerna ekspresija Pgp-a u ćelijama predstavlja jedan od mehanizama razvoja rezistencije na lekove. Iz ovih razloga, potrebno je u ranoj fazi otkrića leka predvideti da li je potencijalni lek supstrat za Pgp, idealno i pre same sinteze. U tu svrhu, tokom poslednje decenije razvijen je veliki broj računarskih modela koji omogućavaju predviđanje transporta posredstvom Pgp-a samo na osnovu hemijske strukture. U ovom radu prikazan je pregled različitih pristupa koji su korišćeni u razvoju modela, razmotrene su njihove prednosti i nedostaci, kao i faktori koji u najvećoj meri utiču na pouzdanost predviđanja. Polispecifičnost ovog transportera predstavlja značajan izazov za većinu metoda računarske hemije. Ipak, dostignut nivo tačnosti modela koji su prikazani u litearaturi ukazuje na činjenicu da oni mogu doprineti racionalizaciji procesa dizajniranja novih lekova. Šira dostupnost eksperimentalnih podataka, kao i kombinovanje različitih pristupa modelovanju transporta, mogu dodatno unaprediti postojeće modele.Ključne reči: P-glikoprotein, računarski modeli, rezistencija, dizajn lekova.

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Towards understanding promiscuity in multidrug efflux pumps

Cited by 114 publications

References 64 publications

Selenoesters and selenoanhydrides as novel multidrug resistance reversing agents: A confirmation study in a colon cancer MDR cell line

Selenoesters and selenoanhydrides as novel multidrug resistance reversing agents: A confirmation study in a colon cancer MDR cell line

Identification of the High-affinity Substrate-binding Site of the Multidrug and Toxic Compound Extrusion (MATE) Family Transporter from Pseudomonas stutzeri

Computational models for predicting drug transport mediated by P-glycoprotein

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