Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Target Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Query: UNIPROT:P33527 (
ABCC1
)
1,164
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
The human multidrug resistance protein 1 (hMRP1) transporter is implicated in cancer multidrug resistance as well as immune responses involving its physiologic substrate, glutathione (GSH)-conjugated leukotriene C
4
(LTC
4
). LTC
4
binds a bipartite site on hMRP1, which a recent cryoelectron microscopy structure of LTC
4
-bound bovine Mrp1 depicts as composed of a positively charged pocket and a hydrophobic (H) pocket that binds the GSH moiety and surrounds the fatty acid moiety, respectively, of LTC
4
. Here, we show that single Ala and Leu substitutions of H-pocket hMRP1-
Met
1093
have no effect on LTC
4
binding or transport. Estrone 3-sulfate transport is also unaffected, but both hMRP1-
Met
1093
mutations eliminate estradiol glucuronide transport, demonstrating that these steroid conjugates have binding sites distinct from each other and from LTC
4
. To eliminate LTC
4
transport by hMRP1, mutation of 3 H-pocket residues was required (W553/M1093/W1246A), indicating that H-pocket amino acids are key to the vastly different affinities of hMRP1 for LTC
4
vs.
GSH alone. Unlike organic anion transport, hMRP1-mediated drug resistance was more diminished by Ala than Leu substitution of
Met
1093
. Although our findings generally support a structure in which H-pocket residues bind the lipid tail of LTC
4
, their critical and differential role in the transport of conjugated estrogens and anticancer drugs remains unexplained.-Conseil, G., Arama-Chayoth, M., Tsfadia, Y., Cole, S. P. C. Structure-guided probing of the leukotriene C
4
binding site in human multidrug resistance protein 1 (MRP1;
ABCC1
).
...
PMID:Structure-guided probing of the leukotriene C
4
binding site in human multidrug resistance protein 1 (MRP1; ABCC1). 3126 44
