37:
244:
228:
505:
cells that belong to the HAE-RND subfamily have been classified, including the multi-drug efflux protein AcrB, the outer membrane protein TolC and the periplasmic adaptor protein AcrA. The TolC and AcrA proteins are also utilized in the tripartite complex in other identified RND efflux proteins. The
302:
helices (TM1-TM12). The periplasmic domain consists of two helices, TM2 and TM8. In addition, the periplasmic domain is made up of six subdomains, PN1, PN2, PC1, PC2, DN, DC, which form a central pore and a dock domain. The central pore is formed by PN1, PN2, PC1, PC2, and together stabilize the
278:
RND pumps are the cytoplasmic residing portion of a complete tripartite complex (Fig. 1) which spreads across the outer-membrane and the inner membrane of gram-negative bacteria, also commonly referred to as the CBA efflux system. The RND protein associates with an outer membrane channel and a
274:
followed by a large extracytoplasmic domain, then six additional TMSs, a second large extracytoplasmic domain, and five final C-terminal TMSs. TM4 governs the specificity for a particular substrate in a given RND protein. Therefore, TM4 can be an indicator for RND specificity without explicit
500:
multi-drug resistance develops from a variety of mechanisms. Particularly concerning is the ability of efflux mechanisms to confer broad-spectrum resistance. RND efflux pumps provide extrusion for a range of compounds. Five protein transporters in
593:
Tseng TT, Gratwick KS, Kollman J, Park D, Nies DH, Goffeau A, Saier MH (August 1999). "The RND permease superfamily: an ancient, ubiquitous and diverse family that includes human disease and development proteins".
560:
and various other bacteria. Unlike other RND proteins Mdt(A) contains a putative ATP-binding site and two C-motifs conserved in its fifth TMS. Mdt is effective at providing the bacteria with resistance to
444:
five RND pumps have been specifically identified: AcrAB, AcrAD, AcrEF, MdtEF, and MdtAB. Although it is not clear how the tripartite complex works in bacteria two mechanisms have been proposed:
152:/amphiphile efflux-1 (gram-negative bacteria), the nodulation factor exporter family (NFE), the SecDF protein-secretion accessory protein family, the hydrophobe/amphiphile efflux-2 family, the
262:
subunits (suggesting they arose as a result of an intragenic tandem duplication event that occurred in the primordial system prior to divergence of the family members) each containing a
459:
and exportation of organic substrates allowed for recent characterization of specific pumps due to their increasing medical relevance. Half of the antibiotic resistance demonstrated in
475:
contain 13 RND transport systems, including one HME-RND and the remaining HAE-RNDs. Among the best identified are the Mex proteins: MexB, MexD, and MexF, which detoxify
180:. Most of the RND superfamily transport systems are made of large polypeptide chains. RND proteins exist primarily in gram-negative bacteria but can also be found in
333:
through the CzcA and later the CnrA protein. The best characterized RND proteins include CzcCBA (Cd, Zn, and Co), CnrCBA (Ni and Co), and NccCBA (Ni, Co and Cd) in
112:
100:
172:. They have a broad substrate spectrum and can lead to the diminished activity of unrelated drug classes if over-expressed. The first reports of drug resistant
283:
adaptor protein, and the association of all three proteins allows the system to export substrates into the external medium, providing a huge advantage for the
979:"The novel Helicobacter pylori CznABC metal efflux pump is required for cadmium, zinc, and nickel resistance, urease modulation, and gastric colonization"
669:
Routh, Mathew David, "Structure, function, and regulation of multidrug export proteins among the RND superfamily in Gram-negative bacteria" (2010).
432:
The RND family plays an important role in producing intrinsic and elevated multi-drug resistance in gram-negative bacteria. The export of
1193:
416:
fusion protein (MFP) CzcB, and the outer membrane factor protein (OMF) CzcC, all of which form the active tripartite complex, and the
1198:
831:
323:. The family includes pumps which export monovalent metals—the Cus system, and pumps which export divalent metals—the Czc system.
545:
The crystallized AcrB protein, provides insight into the mechanism of action of HAE-RND proteins, and other RND family proteins.
1183:
928:"Two RND proteins involved in heavy metal efflux in Caulobacter crescentus belong to separate clusters within proteobacteria"
623:"Overexpression of resistance-nodulation-cell division pump AdeFGH confers multidrug resistance in Acinetobacter baumannii"
1188:
17:
1131:"Mdt(A), a new efflux protein conferring multiple antibiotic resistance in Lactococcus lactis and Escherichia coli"
36:
291:
709:"Differential regulation of six heavy metal efflux systems in the response of Myxococcus xanthus to copper"
467:
342:
181:
137:
542:. The ways in which the lipophilic domains of the substrate and the RND pumps is not completely defined.
299:
133:
977:
Stähler FN, Odenbreit S, Haas R, Wilrich J, Van Vliet AH, Kusters JG, Kist M, Bereswill S (July 2006).
882:
720:
160:
family, and the hydrophobe/amphiphile efflux-3 family. These RND systems are involved in maintaining
388:
349:
173:
145:
555:
259:
1160:
1111:
1062:
1008:
959:
908:
847:
827:
796:
746:
652:
603:
326:
234:
RND inner-membrane protein, outer-membrane fusion protein, & periplasmic adaptor protein.
221:
1150:
1142:
1101:
1093:
1052:
1042:
998:
990:
949:
939:
898:
890:
837:
819:
786:
736:
728:
642:
634:
507:
496:
476:
413:
316:
169:
141:
553:
Mdt(A) is an efflux pump that confers resistance to a variety of drugs. It is expressed in
566:
539:
81:
686:
886:
871:"Crystal structures of the CusA efflux pump suggest methionine-mediated metal transport"
724:
1106:
1081:
1057:
1030:
1003:
978:
954:
927:
903:
870:
842:
741:
708:
647:
622:
456:
165:
791:
774:
200:
The RND protein dictates the substrate for the completed transport systems including:
105:
1177:
1155:
1130:
1146:
866:
574:
570:
562:
531:
506:
AcrAB-TolC efflux system is responsible for the efflux of antimicrobial drugs like
227:
117:
69:
1097:
93:
814:
Nikaido H (2011). "Structure and mechanism of RND-type multidrug efflux pumps".
511:
480:
335:
267:
177:
161:
157:
243:
823:
523:
479:. It is proposed that the MexB systems demonstrates substrate specificity for
437:
433:
362:
based on the location of multiple substrate binding sites on the RND protein.
320:
304:
295:
271:
255:
217:
213:
205:
149:
1047:
392:. The CznC and CznA proteins play the dominating role in nickel homeostasis.
294:
providing valuable structural information of HME-RND pumps. CusA exists as a
270:. Of the twelve helices there is a single transmembrane spanner (TMS) at the
944:
527:
519:
515:
359:
355:
280:
263:
189:
153:
1164:
1115:
1066:
1012:
963:
912:
851:
800:
750:
656:
607:
707:
Moraleda-Muñoz A, Pérez J, Extremera AL, Muñoz-Dorado J (September 2010).
412:. The CzcCBA operon includes: CzcA (the RND family specific protein), the
994:
732:
638:
621:
Coyne S, Rosenfeld N, Lambert T, Courvalin P, PĂ©richon B (October 2010).
577:. The source of energy for active efflux by Mdt(A) is currently unknown.
284:
894:
220:
compounds are carried out by the HAE-RND subfamily. While the efflux of
535:
461:
409:
371:
185:
865:
Long F, Su CC, Zimmermann MT, Boyken SE, Rajashankar KR, Jernigan RL,
674:
483:; while the MexD-system expresses specificity for cepheme compounds.
421:
401:
383:
379:
44:: An HAE-RND subclass protein involved in drug and amphiphilic efflux
201:
687:"2.A.6 The Resistance-Nodulation-Cell Division (RND) Superfamily"
405:
375:
209:
88:
76:
63:
290:
The CusA protein, a HME-RND member transporter, was able to be
176:
were reported in the 1940s after the first mass production of
1086:
Biochimica et
Biophysica Acta (BBA) - Proteins and Proteomics
816:
Advances in
Enzymology and Related Areas of Molecular Biology
534:
antibiotics. Other substrates include dyes, detergents, some
354:
It has been proposed that metal-ion efflux occurs from the
148:
includes seven families: the heavy metal efflux (HME), the
1031:"The ins and outs of RND efflux pumps in Escherichia coli"
1129:
Perreten V, Schwarz FV, Teuber M, Levy SB (April 2001).
926:
Valencia EY, Braz VS, Guzzo C, Marques MV (April 2013).
775:"Efflux-mediated heavy metal resistance in prokaryotes"
254:
RND proteins are large and can include more than 1000
702:
700:
329:
resistance by the RND family was first discovered in
18:
Resistance-Nodulation-Cell
Division Superfamily (RND)
596:
Journal of
Molecular Microbiology and Biotechnology
111:
99:
87:
75:
62:
54:
49:
29:
1029:Anes J, McCusker MP, Fanning S, Martins M (2015).
319:in metal ion efflux powered by a proton-substrate
440:substrates is governed by the HAE-RND family. In
140:and located in the cytoplasmic membrane, that
258:residues. They are generally composed of two
8:
1024:
1022:
315:The HME-RND family functions as the central
768:
766:
764:
762:
760:
275:knowledge of the remainder of the protein.
1082:"Mechanisms of RND multidrug efflux pumps"
1154:
1105:
1056:
1046:
1002:
953:
943:
902:
841:
790:
740:
646:
386:modulation, and gastric colonization by
370:The Czn system maintains homeostasis of
242:
226:
132:) family transporters are a category of
585:
471:was attributed to RND efflux proteins.
347:and Czn (Cd, Zn, and Ni resistance) in
818:. Vol. 77. Wiley. pp. 1–60.
713:Applied and Environmental Microbiology
26:
1135:Antimicrobial Agents and Chemotherapy
627:Antimicrobial Agents and Chemotherapy
7:
1080:Nikaido H, Takatsuka Y (May 2009).
691:Transporter Classification Database
675:http://lib.dr.iastate.edu/etd/11401
671:Graduate Theses and Dissertations.
266:loop adjacent to 12 transmembrane
25:
424:is regulated through metal ions.
549:Multidrug transport (Mdt) efflux
298:with each unit consisting of 12
35:
1147:10.1128/AAC.45.4.1109-1114.2001
382:resistance; it is involved in
340:Czr (Cd and Zn resistance) in
126:Resistance-nodulation-division
1:
792:10.1016/s0168-6445(03)00048-2
303:trimeric organization of the
1098:10.1016/j.bbapap.2008.10.004
455:HAE-RNDs involvement in the
250:: HAE-RND subclass protein
136:, especially identified in
1215:
1194:Integral membrane proteins
400:Czc confers resistance to
311:Metal ion efflux (HME-RND)
232:Triparitate Complex Model:
1035:Frontiers in Microbiology
824:10.1002/9780470920541.ch1
779:FEMS Microbiology Reviews
428:Drug resistance (HAE-RND)
34:
1199:Antimicrobial resistance
1048:10.3389/fmicb.2015.00587
164:of the cell, removal of
30:RND permease superfamily
945:10.1186/1471-2180-13-79
239:Mechanism and structure
983:Infection and Immunity
468:Pseudomonas aeruginosa
450:Adaptor Wrapping Model
446:Adaptor Bridging Model
343:Pseudomonas aeruginosa
251:
235:
224:are preformed HME-RND.
182:gram-positive bacteria
170:virulence determinants
138:Gram-negative bacteria
134:bacterial efflux pumps
1184:Protein superfamilies
773:Nies DH (June 2003).
246:
230:
995:10.1128/IAI.02025-05
733:10.1128/AEM.00753-10
639:10.1128/AAC.00155-10
465:hospital strains of
420:. Expression of the
174:bacterial infections
144:substrates. The RND
895:10.1038/nature09395
887:2010Natur.467..484L
725:2010ApEnM..76.6069M
350:Helicobacter pylori
1189:Bacterial proteins
869:(September 2010).
477:organic substances
252:
236:
142:actively transport
248:Crystallized CusA
123:
122:
42:Crystallized AcrB
16:(Redirected from
1206:
1169:
1168:
1158:
1126:
1120:
1119:
1109:
1077:
1071:
1070:
1060:
1050:
1026:
1017:
1016:
1006:
974:
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967:
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947:
932:BMC Microbiology
923:
917:
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906:
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856:
855:
845:
811:
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804:
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770:
755:
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744:
704:
695:
694:
683:
677:
667:
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650:
618:
612:
611:
590:
540:steroid hormones
536:organic solvents
331:R. metallidurans
168:, and export of
39:
27:
21:
1214:
1213:
1209:
1208:
1207:
1205:
1204:
1203:
1174:
1173:
1172:
1128:
1127:
1123:
1079:
1078:
1074:
1028:
1027:
1020:
976:
975:
971:
925:
924:
920:
881:(7314): 484–8.
864:
863:
859:
834:
813:
812:
808:
785:(2–3): 313–39.
772:
771:
758:
719:(18): 6069–76.
706:
705:
698:
685:
684:
680:
668:
664:
633:(10): 4389–93.
620:
619:
615:
592:
591:
587:
583:
567:chloramphenicol
551:
492:
430:
398:
368:
313:
241:
212:. Transport of
198:
166:toxic compounds
101:OPM superfamily
45:
23:
22:
15:
12:
11:
5:
1212:
1210:
1202:
1201:
1196:
1191:
1186:
1176:
1175:
1171:
1170:
1141:(4): 1109–14.
1121:
1072:
1018:
989:(7): 3845–52.
969:
918:
857:
832:
806:
756:
696:
678:
662:
613:
584:
582:
579:
550:
547:
491:
485:
457:detoxification
429:
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397:
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367:
364:
312:
309:
240:
237:
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109:
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97:
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24:
14:
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3:
2:
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1140:
1136:
1132:
1125:
1122:
1117:
1113:
1108:
1103:
1099:
1095:
1092:(5): 769–81.
1091:
1087:
1083:
1076:
1073:
1068:
1064:
1059:
1054:
1049:
1044:
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1005:
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880:
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868:
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839:
835:
833:9780470920541
829:
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730:
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688:
682:
679:
676:
673:Paper 11401.
672:
666:
663:
658:
654:
649:
644:
640:
636:
632:
628:
624:
617:
614:
609:
605:
602:(1): 107–25.
601:
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572:
568:
564:
559:
557:
548:
546:
543:
541:
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525:
521:
517:
513:
509:
504:
499:
498:
489:
486:
484:
482:
478:
474:
473:P. aeruginosa
470:
469:
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463:
458:
453:
451:
447:
443:
439:
435:
427:
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351:
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300:transmembrane
297:
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57:
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43:
38:
33:
28:
19:
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1038:
1034:
986:
982:
972:
935:
931:
921:
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860:
815:
809:
782:
778:
716:
712:
690:
681:
670:
665:
630:
626:
616:
599:
595:
588:
575:streptomycin
571:lincosamides
563:tetracycline
554:
552:
544:
532:fusidic acid
508:penicillin G
502:
495:
493:
487:
481:beta-lactams
472:
466:
460:
454:
449:
445:
441:
431:
417:
399:
387:
369:
348:
341:
334:
330:
325:
317:protein pump
314:
292:crystallized
289:
277:
253:
247:
231:
222:heavy metals
199:
129:
125:
124:
58:RND_Permease
41:
512:cloxacillin
438:hydrophobic
434:amphiphilic
336:Cupriavidus
327:Heavy metal
281:periplasmic
264:periplasmic
218:amphiphilic
214:hydrophobic
206:xenobiotics
178:antibiotics
162:homeostasis
158:homeostasis
146:superfamily
113:OPM protein
50:Identifiers
1178:Categories
581:References
524:novobiocin
520:macrolides
305:homotrimer
296:homotrimer
272:N-terminus
260:homologous
256:amino acid
202:metal ions
190:eukaryotes
154:eukaryotic
150:hydrophobe
558:, E. coli
556:L. lactis
528:linezolid
516:nafcillin
418:czcoperon
389:H. pylori
360:periplasm
356:cytoplasm
1165:11257023
1116:19026770
1067:26113845
1013:16790756
964:23578014
913:20865003
852:21692366
801:12829273
751:20562277
657:20696879
608:10941792
414:membrane
321:antiport
285:bacteria
196:Function
82:5067.1.1
1107:2696896
1058:4462101
1041:: 587.
1004:1489693
955:3637150
904:2946090
883:Bibcode
843:3122131
742:2937488
721:Bibcode
648:2944555
503:E. coli
497:E. coli
488:E. coli
462:in vivo
442:E. coli
410:Cadmium
372:Cadmium
268:helices
186:archaea
156:sterol
1163:
1153:
1114:
1104:
1065:
1055:
1011:
1001:
962:
952:
938:: 79.
911:
901:
875:Nature
850:
840:
830:
799:
749:
739:
655:
645:
606:
538:, and
530:, and
490:– AcrB
422:operon
408:, and
402:Cobalt
396:CzcCBA
384:Urease
380:Nickel
378:, and
366:CznCBA
188:, and
70:CL0322
55:Symbol
1156:90432
867:Yu EW
210:drugs
94:2.A.6
1161:PMID
1112:PMID
1090:1794
1063:PMID
1009:PMID
960:PMID
909:PMID
848:PMID
828:ISBN
797:PMID
747:PMID
653:PMID
604:PMID
573:and
448:and
436:and
406:Zinc
376:Zinc
358:and
216:and
118:2gif
89:TCDB
77:ECOD
66:clan
64:Pfam
1151:PMC
1143:doi
1102:PMC
1094:doi
1053:PMC
1043:doi
999:PMC
991:doi
950:PMC
940:doi
899:PMC
891:doi
879:467
838:PMC
820:doi
787:doi
737:PMC
729:doi
643:PMC
635:doi
494:In
208:or
130:RND
1180::
1159:.
1149:.
1139:45
1137:.
1133:.
1110:.
1100:.
1088:.
1084:.
1061:.
1051:.
1037:.
1033:.
1021:^
1007:.
997:.
987:74
985:.
981:.
958:.
948:.
936:13
934:.
930:.
907:.
897:.
889:.
877:.
873:.
846:.
836:.
826:.
795:.
783:27
781:.
777:.
759:^
745:.
735:.
727:.
717:76
715:.
711:.
699:^
689:.
651:.
641:.
631:54
629:.
625:.
598:.
569:,
565:,
526:,
522:,
518:,
514:,
510:,
452:.
404:,
374:,
307:.
287:.
204:,
192:.
184:,
106:16
1167:.
1145::
1118:.
1096::
1069:.
1045::
1039:6
1015:.
993::
966:.
942::
915:.
893::
885::
854:.
822::
803:.
789::
753:.
731::
723::
693:.
659:.
637::
610:.
600:1
352:.
345:,
338:,
128:(
20:)
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