Providing a molecular mechanism for P-glycoprotein; why would I bother?

被引：32
作者：
Callaghan, Richard [1 ]
机构：
[1] Australian Natl Univ, Res Sch Biol, Div Biomed Sci & Biochem, Canberra, ACT 0200, Australia
来源：
BIOCHEMICAL SOCIETY TRANSACTIONS | 2015年 / 43卷
基金：
英国惠康基金;
关键词：
ATP-binding cassette (ABC) protein; cancer chemotherapy; membrane transport; molecular mechanism; multi-drug resistance; permeability (P)-glycoprotein; MULTIDRUG-RESISTANCE TRANSPORTER; NUCLEOTIDE-BINDING DOMAINS; OVARY CELL MUTANTS; CRYSTAL-STRUCTURE; ABC TRANSPORTER; ATPASE ACTIVITY; HIGH-AFFINITY; DRUG-BINDING; TUMOR-CELLS; PROTEIN;
D O I：
10.1042/BST20150131
中图分类号：
Q5 [生物化学]; Q7 [分子生物学];
学科分类号：
071010 ; 081704 ;
摘要：
It is almost 40 years since the drug efflux pump P-glycoprotein (permeability glycoprotein or P-gp) was shown to confer multi-drug resistance in cancer cells. This protein has been one of the most extensively investigated transport proteins due to its intriguing mechanism and its affect in oncology. P-gp is known to interact with over 300 compounds and the ability to achieve this has not yet been revealed. Following the binding of substrate and nucleotide, a complex series of conformational changes in the membrane and cytosolic domains translocates substrate across the membrane. Despite over 30 years of biochemical investigation, the availability of structural data and a plethora of chemical tools to modulate its function, the molecular mechanism remains a mystery. In addition, overcoming its activity in resistant cancer cells has not been achieved in the clinic, thereby garnering some degree of pessimism in the field. This review highlights the progress that has been achieved in understanding this complex protein and the value of undertaking molecular studies.
引用
收藏
页码：995 / 1002
页数：8
相关论文
共 54 条
[11]   Structure of a bacterial multidrug ABC transporter [J].
Dawson, Roger J. P. ;
Locher, Kaspar P. .
NATURE, 2006, 443 (7108) :180-185
[12]   Evidence for two nonidentical drug-interaction sites in the human P-glycoprotein [J].
Dey, S ;
Ramachandra, M ;
Pastan, I ;
Gottesman, MM ;
Ambudkar, SV .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1997, 94 (20) :10594-10599
[13]   Crystal structure of MalK, the ATPase subunit of the trehalose/maltose ABC transporter of the archaeon Thermococcus litoralis [J].
Diederichs, K ;
Diez, J ;
Greller, G ;
Müller, C ;
Breed, J ;
Schnell, C ;
Vonrhein, C ;
Boos, W ;
Welte, W .
EMBO JOURNAL, 2000, 19 (22) :5951-5961
[14]  
DOIGE CA, 1992, BIOCHIM BIOPHYS ACTA, V1109, P149, DOI 10.1016/0005-2736(92)90078-Z
[15]   A multidrug resistance transporter from human MCF-7 breast cancer cells [J].
Doyle, LA ;
Yang, WD ;
Abruzzo, LV ;
Krogmann, T ;
Gao, YM ;
Rishi, AK ;
Ross, DD .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1998, 95 (26) :15665-15670
[16]   P-GLYCOPROTEIN POSSESSES A 1,4-DIHYDROPYRIDINE-SELECTIVE DRUG ACCEPTOR SITE WHICH IS ALLOSERICALLY COUPLED TO A VINCA-ALKALOID-SELECTIVE BINDING-SITE [J].
FERRY, DR ;
RUSSELL, MA ;
CULLEN, MH .
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 1992, 188 (01) :440-445
[17]   Competitive and non-competitive inhibition of the multidrug-resistance-associated P-glycoprotein ATPase - Further experimental evidence for a multisite model [J].
Garrigos, M ;
Mir, LM ;
Orlowski, S .
EUROPEAN JOURNAL OF BIOCHEMISTRY, 1997, 244 (02) :664-673
[18]  
GREENBERGER LM, 1993, J BIOL CHEM, V268, P11417
[19]   MAMMALIAN MULTIDRUG RESISTANCE GENE - COMPLETE CDNA SEQUENCE INDICATES STRONG HOMOLOGY TO BACTERIAL TRANSPORT PROTEINS [J].
GROS, P ;
CROOP, J ;
HOUSMAN, D .
CELL, 1986, 47 (03) :371-380
[20]  
HAMADA H, 1988, J BIOL CHEM, V263, P1454
123456