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Epitope mapping of monoclonal antibodies specific for the 190-kDa multidrug resistance protein (MRP).

ABSTRACT: Inherent or acquired resistance to multiple natural product drugs in human tumour cells is often associated with increased expression of multidrug resistance protein (MRP), a 190-kDa integral membrane protein that belongs to the ATP-binding cassette (ABC) superfamily of transport proteins. Both clinical and experimental investigations of MRP have been facilitated by several monoclonal antibodies (MAbs) generated against intracellular epitopes of the molecule. Recently, however, several new ABC transporters that are quite closely related to MRP have been identified, raising concerns about the specificity of the MRP-reactive MAbs. In the present study, we have mapped the epitopes of MAbs MRPr1 and MRPm6 to the decapeptides 238GSDLWSLNKE247 (located in the intracellular loop between the first and second membrane-spanning domains of MRP) and 1511PSDLLQQRGL1520 (located near the carboxy terminus of MRP) respectively. Alignment of the MRPr1 and MRPm6 epitope sequences with the comparable regions in mammalian ABC proteins most closely related to MRP indicates that, with the exception of murine mrp, the sequences are poorly conserved. We conclude that MAbs MRPm6 and MRPr1, together with MAb QCRL-1, which has previously been mapped to the heptapeptide 918SSYSGDI924, remain highly specific probes for detection of different regions of the MRP molecule.

SUBMITTER: Hipfner DR

PROVIDER: S-EPMC2063015 | biostudies-other | 1998 Nov

REPOSITORIES: biostudies-other

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Epitope mapping of monoclonal antibodies specific for the 190-kDa multidrug resistance protein (MRP).

Hipfner D R DR Gao M M Scheffer G G Scheper R J RJ Deeley R G RG Cole S P SP

British journal of cancer 19981101 9

Inherent or acquired resistance to multiple natural product drugs in human tumour cells is often associated with increased expression of multidrug resistance protein (MRP), a 190-kDa integral membrane protein that belongs to the ATP-binding cassette (ABC) superfamily of transport proteins. Both clinical and experimental investigations of MRP have been facilitated by several monoclonal antibodies (MAbs) generated against intracellular epitopes of the molecule. Recently, however, several new ABC t ...[more]

PMID: 9820168

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Project description:Dengue virus (DV) infection causes a spectrum of clinical diseases ranging from dengue fever to a life-threatening dengue hemorrhagic fever. Four distinct serotypes (DV1-4), which have similar genome sequences and envelope protein (E protein) antigenic properties, were divided. Among these 4 serotypes, DV1 usually causes predominant infections and fast diagnosis and effective treatments are urgently required to prevent further hospitalization and casualties.To develop antibodies specifically targeting and neutralizing DV1, we immunized mice with UV-inactivated DV1 viral particles and recombinant DV1 E protein from residue 1 to 395 (E395), and then generated 12 anti-E monoclonal antibodies (mAbs) as the candidates for a series of characterized assays such as ELISA, dot blot, immunofluorescence assay, western blot, and foci forming analyses.Among the mAbs, 10 out of 12 showed cross-reactivity to four DV serotypes as well as Japanese encephalitis virus (JEV) in different cross-reactivity patterns. Two particular mAbs, DV1-E1 and DV1-E2, exhibited strong binding specificity and neutralizing activity against DV1 and showed no cross-reactivity to DV2, DV3, DV4 or JEV-infected cells as characterized by ELISA, dot blot, immunofluorescence assay, western blot, and foci forming analyses. Using peptide coated indirect ELISA, we localized the neutralizing determinants of the strongly inhibitory mAbs to a sequence-unique epitope on the later-ridge of domain III of the DV1 E protein, centered near residues T346 and D360 (346TQNGRLITANPIVTD360). Interestingly, the amino acid sequence of the epitope region is highly conserved among different genotypes of DV1 but diverse from DV2, DV3, DV4 serotypes and other flaviviruses.Our results showed two selected mAbs DV1-E1 and DV1-E2 can specifically target and significantly neutralize DV1. With further research these two mAbs might be applied in the development of DV1 specific serologic diagnosis and used as a feasible treatment option for DV1 infection. The identification of DV1 mAbs epitope with key residues can also provide vital information for vaccine design.

Dataset Information

Epitope mapping of monoclonal antibodies specific for the 190-kDa multidrug resistance protein (MRP).

Publications

Epitope mapping of monoclonal antibodies specific for the 190-kDa multidrug resistance protein (MRP).

Similar Datasets

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