ABCB1

Target not currently curated in GtoImmuPdb

Target id: 768

Nomenclature: ABCB1

Abbreviated Name: MDR1, PGP1

Systematic Nomenclature: ABCB1

Gene and Protein Information
Species	TM	AA	Chromosomal Location	Gene Symbol	Gene Name	Reference
Human	12	1280	7q21.12	ABCB1	ATP binding cassette subfamily B member 1
Mouse	12	1276	5 3.43 cM	Abcb1a	ATP-binding cassette, sub-family B (MDR/TAP), member 1A
Rat	-	-		Abcb1a	ATP binding cassette subfamily B member 1A

Previous and Unofficial Names
P-glycoprotein 1 \| ABC20 \| CD243 \| CLCS \| GP170 \| MDR1 \| PGY1 \| colchicin sensitivity \| multidrug resistance protein 1 \| Abcb1 \| ATP-binding cassette, sub-family B (MDR/TAP), member 1 \| ATP-binding cassette, subfamily B (MDR/TAP), member 1A \| Mdr1a \| multiple drug resistant 1a \| Evi32 \| MDR3 \| mdr-3 \| Pgp \| Pgy3 \| Pgy-3 \| P-gp \| Abcb1a \| ATP binding cassette subfamily B member 1 \| ATP-binding cassette

P-glycoprotein 1 | ABC20 | CD243 | CLCS | GP170 | MDR1 | PGY1 | colchicin sensitivity | multidrug resistance protein 1 | Abcb1 | ATP-binding cassette, sub-family B (MDR/TAP), member 1 | ATP-binding cassette, subfamily B (MDR/TAP), member 1A | Mdr1a | multiple drug resistant 1a | Evi32 | MDR3 | mdr-3 | Pgp | Pgy3 | Pgy-3 | P-gp | Abcb1a | ATP binding cassette subfamily B member 1 | ATP-binding cassette

Database Links
Alphafold	P08183 (Hs), P21447 (Mm)
ChEMBL Target	CHEMBL4302 (Hs), CHEMBL2573 (Mm)
DrugBank Target	P08183 (Hs)
Ensembl Gene	ENSG00000085563 (Hs), ENSMUSG00000040584 (Mm), ENSRNOG00000008012 (Rn)
Entrez Gene	5243 (Hs), 18671 (Mm), 170913 (Rn)
Human Protein Atlas	ENSG00000085563 (Hs)
KEGG Gene	hsa:5243 (Hs), mmu:18671 (Mm), rno:170913 (Rn)
OMIM	171050 (Hs)
Pharos	P08183 (Hs)
UniProtKB	P08183 (Hs), P21447 (Mm)
Wikipedia	ABCB1 (Hs)

Selected 3D Structures

Image of receptor 3D structure from RCSB PDB

Description:	Molecular structure of human P-glycoprotein (ABCB1) in the ATP-bound, outward-facing conformation
PDB Id:	6C0V
Ligand:	ATP
Resolution:	3.4Å
Species:	Human
References:	3

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Inhibitors

Key to terms and symbols

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Ligand		Sp.	Action	Value	Parameter	Reference
zosuquidar		Hs	Inhibition	7.2	pK_i	2
⤷	pK_i 7.2 (K_i 5.9x10^-8 M) [2]
valspodar		Hs	Inhibition	5.9	pK_i	10
⤷	pK_i 5.9 (K_i 1.3x10^-6 M) [10]
WS-898		Hs	Inhibition	8.3	pIC₅₀	9
⤷	pIC₅₀ 8.3 (IC₅₀ 5x10^-9 M) [9]
tariquidar		Mm	Inhibition	7.4	pIC₅₀	5
⤷	pIC₅₀ 7.4 (IC₅₀ 3.8x10^-8 M) [5] Description: Measuring the effect of XR9576 on accumulation of [3H] daunorubicin in the multidrug resistant mouse mammary carcinoma cell line EMT6/AR1.0
compound 14 [PMID: 30925062]		Hs	Competitive	5.8 – 6.2	pIC₅₀	7
⤷	pIC₅₀ 6.2 (IC₅₀ 6.76x10^-7 M) [7] Description: Measuring inhibition of cyclosporine A transport in A2780/ADR cells expressing hABCB1. pIC₅₀ 5.8 (IC₅₀ 1.73x10^-6 M) [7] Description: Measuring inhibition of calcein AM transport in A2780/ADR cells expressing hABCB1.
biricodar		Hs	Inhibition	5.3	pIC₅₀	8
⤷	pIC₅₀ 5.3 (IC₅₀ 5x10^-6 M) [8]

View species-specific inhibitor tables

Inhibitor Comments

Laniquidar (R101933) is a third generation P-gp inhibitor that reached phase 2 clinical evaluation.

Biologically Significant Variant Comments
Nonsense mutation in ABCB1 has been described in collie dogs [4,6] and when these animals are treated with ivermectin they develop potentially fatal neurologic disorders, due to a toxic accumulation of ivermectin in the central nervous system. Similar ivermectin-induced pathology has been noted in humans. In 2020 mutated human ABCB1 alleles were identified in a patient who developed serious ivermectin toxicity following a single oral dose of the drug. Genetic analysis revealed that this patient harboured a different nonsense alteration in each copy of their ABCB1 genes. Both mutations generated premature stop codons and truncated transporter proteins that lacked the C-terminal nucleotide-binding domain, rendering the proteins incapable of drug-transport [1].

Biologically Significant Variant Comments

Nonsense mutation in ABCB1 has been described in collie dogs [4,6] and when these animals are treated with ivermectin they develop potentially fatal neurologic disorders, due to a toxic accumulation of ivermectin in the central nervous system. Similar ivermectin-induced pathology has been noted in humans. In 2020 mutated human ABCB1 alleles were identified in a patient who developed serious ivermectin toxicity following a single oral dose of the drug. Genetic analysis revealed that this patient harboured a different nonsense alteration in each copy of their ABCB1 genes. Both mutations generated premature stop codons and truncated transporter proteins that lacked the C-terminal nucleotide-binding domain, rendering the proteins incapable of drug-transport [1].

References

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1. Baudou E, Lespine A, Durrieu G, André F, Gandia P, Durand C, Cunat S. (2020) Serious Ivermectin Toxicity and Human ABCB1 Nonsense Mutations. N Engl J Med, 383: 787-789 [Epub ahead of print]. DOI: 10.1056/NEJMc1917344

2. Dantzig AH, Shepard RL, Law KL, Tabas L, Pratt S, Gillespie JS, Binkley SN, Kuhfeld MT, Starling JJ, Wrighton SA. (1999) Selectivity of the multidrug resistance modulator, LY335979, for P-glycoprotein and effect on cytochrome P-450 activities. J Pharmacol Exp Ther, 290 (2): 854-62. [PMID:10411602]

3. Kim Y, Chen J. (2018) Molecular structure of human P-glycoprotein in the ATP-bound, outward-facing conformation. Science, 359 (6378): 915-919. [PMID:29371429]

4. Mealey KL. (2004) Therapeutic implications of the MDR-1 gene. J Vet Pharmacol Ther, 27 (5): 257-64. [PMID:15500562]

5. Roe M, Folkes A, Ashworth P, Brumwell J, Chima L, Hunjan S, Pretswell I, Dangerfield W, Ryder H, Charlton P. (1999) Reversal of P-glycoprotein mediated multidrug resistance by novel anthranilamide derivatives. Bioorg Med Chem Lett, 9 (4): 595-600. [PMID:10098671]

6. Schinkel AH, Smit JJ, van Tellingen O, Beijnen JH, Wagenaar E, van Deemter L, Mol CA, van der Valk MA, Robanus-Maandag EC, te Riele HP et al.. (1994) Disruption of the mouse mdr1a P-glycoprotein gene leads to a deficiency in the blood-brain barrier and to increased sensitivity to drugs. Cell, 77 (4): 491-502. [PMID:7910522]

7. Silbermann K, Stefan SM, Elshawadfy R, Namasivayam V, Wiese M. (2019) Identification of Thienopyrimidine Scaffold as an Inhibitor of the ABC Transport Protein ABCC1 (MRP1) and Related Transporters Using a Combined Virtual Screening Approach. J Med Chem, 62 (9): 4383-4400. [PMID:30925062]

8. Wang S, Ryder H, Pretswell I, Depledge P, Milton J, Hancox TC, Dale I, Dangerfield W, Charlton P, Faint R et al.. (2002) Studies on quinazolinones as dual inhibitors of Pgp and MRP1 in multidrug resistance. Bioorg Med Chem Lett, 12 (4): 571-4. [PMID:11844674]

9. Wang S, Wang SQ, Teng QX, Lei ZN, Chen ZS, Chen XB, Liu HM, Yu B. (2021) Discovery of the Triazolo[1,5-a]Pyrimidine-Based Derivative WS-898 as a Highly Efficacious and Orally Bioavailable ABCB1 Inhibitor Capable of Overcoming Multidrug Resistance. J Med Chem, [Epub ahead of print]. DOI: 10.1021/acs.jmedchem.1c01498 [PMID:34723530]

10. Wigler PW. (1999) PSC833, cyclosporin A, and dexniguldipine effects on cellular calcein retention and inhibition of the multidrug resistance pump in human leukemic lymphoblasts. Biochem Biophys Res Commun, 257 (2): 410-3. [PMID:10198227]

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