ABCB1 p.Tyr444Arg
| Predicted by SNAP2: | A: D (80%), C: D (75%), D: D (91%), E: D (91%), F: D (71%), G: D (85%), H: D (80%), I: D (80%), K: D (91%), L: D (80%), M: D (75%), N: D (80%), P: D (91%), Q: D (85%), R: D (91%), S: D (85%), T: D (85%), V: D (80%), W: D (80%), |
| Predicted by PROVEAN: | A: D, C: D, D: D, E: D, F: D, G: D, H: D, I: D, K: D, L: D, M: D, N: D, P: D, Q: D, R: D, S: D, T: D, V: D, W: D, |
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[hide] In silico screening for inhibitors of p-glycoprote... Mol Pharmacol. 2014 Dec;86(6):716-26. doi: 10.1124/mol.114.095414. Epub 2014 Sep 30. Brewer FK, Follit CA, Vogel PD, Wise JG
In silico screening for inhibitors of p-glycoprotein that target the nucleotide binding domains.
Mol Pharmacol. 2014 Dec;86(6):716-26. doi: 10.1124/mol.114.095414. Epub 2014 Sep 30., [PMID:25270578]
Abstract [show]
Multidrug resistances and the failure of chemotherapies are often caused by the expression or overexpression of ATP-binding cassette transporter proteins such as the multidrug resistance protein, P-glycoprotein (P-gp). P-gp is expressed in the plasma membrane of many cell types and protects cells from accumulation of toxins. P-gp uses ATP hydrolysis to catalyze the transport of a broad range of mostly hydrophobic compounds across the plasma membrane and out of the cell. During cancer chemotherapy, the administration of therapeutics often selects for cells which overexpress P-gp, thereby creating populations of cancer cells resistant to a variety of chemically unrelated chemotherapeutics. The present study describes extremely high-throughput, massively parallel in silico ligand docking studies aimed at identifying reversible inhibitors of ATP hydrolysis that target the nucleotide-binding domains of P-gp. We used a structural model of human P-gp that we obtained from molecular dynamics experiments as the protein target for ligand docking. We employed a novel approach of subtractive docking experiments that identified ligands that bound predominantly to the nucleotide-binding domains but not the drug-binding domains of P-gp. Four compounds were found that inhibit ATP hydrolysis by P-gp. Using electron spin resonance spectroscopy, we showed that at least three of these compounds affected nucleotide binding to the transporter. These studies represent a successful proof of principle demonstrating the potential of targeted approaches for identifying specific inhibitors of P-gp.
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No. Sentence Comment
289 TABLE 2 Identification of protein residues in P-gp that were within 5.0 &#c5; of docked inhibitors Compound Compound 19 (ATP-binding site) Compound 29 (Allosteric binding site) Compound 34 (ADP-binding site) Compound 45 (ATP-binding site) Residues within 5.0 &#c5; of docked inhibitors ILE 160 THR 422 ARG 262 ILE 160 GLY 161 VAL 423 THR 483 GLY 161 ASP 164 ALA 424 LEU 516 ASP 164 PHE 399 LEU 552 PRO 517 PHE 399 TYR 401 LEU 554 HIS 518 TYR 401 PRO 402 THR 563 ASP 521 PRO 402 ILE 409 GLU 566 THR 522 ILE 409 ASN 428 ALA 567 LEU 523 LEU 410 SER 429 VAL 569 VAL 524 ASN 428 GLY 430 GLN 570 GLY 525 SER 429 CYS 431 VAL 571 GLU 526 GLY 430 GLY 432 LEU 573 ALA 529 CYS 431 LYS 433 ASP 574 GLN 530 GLY 432 SER 434 ARG 577 LEU 531 LYS 433 THR 435 THR 582 VAL 801 SER 434 GLN 438 ILE 583 SER 802 THR 435 LEU 443 VAL 584 TRP 803 THR 436 TYR 444 ARG 588 PHE 804 GLN 438 GLN 475 SER 590 ASP 805 TYR 444 GLU 556 THR 591 ASN 809 GLN 475 ILE 585 VAL 592 ASN 1043 GLU 556 HIS 587 ARG 593 TYR 1044 ILE 585 PHE 601 ASN 594 PRO 1045 HIS 587 ARG 905 ALA 595 ARG 1047 ARG 905 ILE 1127 ASP 596 VAL 1052 ILE 1127 PHE 1157 VAL 1273 SER 1077 PHE 1157 ILE 1158 GLN 1274 THR 1078 ILE 1158 LEU 1161 GLY 1276 GLN 1081 LEU 1161 PRO 1162 THR 1277 TYR 1087 PRO 1162 ASN 1163 LYS 1278 GLN 1118 ASN 1163 THR 1167 ARG 1279 LYS 1164 VAL 1169 GLN 1280 THR 1167 THR 1174 THR 1174 GLN 1175 GLN 1175 LEU 1176 LEU 1176 SER 1177 SER 1177 GLY 1178 GLY 1178 GLY 1179 GLY 1179 GLN 1180 GLN 1180 Other groups have shown that flavonoids are strong modulators of P-gp activity and that they interact with the NBDs of the enzyme (Di Pietro et al., 2002).
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ABCB1 p.Tyr444Arg 25270578:289:830
status: NEW[hide] The Transmission Interfaces Contribute Asymmetrica... J Biol Chem. 2015 Jul 3;290(27):16954-63. doi: 10.1074/jbc.M115.652602. Epub 2015 May 18. Loo TW, Clarke DM
The Transmission Interfaces Contribute Asymmetrically to the Assembly and Activity of Human P-glycoprotein.
J Biol Chem. 2015 Jul 3;290(27):16954-63. doi: 10.1074/jbc.M115.652602. Epub 2015 May 18., [PMID:25987565]
Abstract [show]
P-glycoprotein (P-gp; ABCB1) is an ABC drug pump that protects us from toxic compounds. It is clinically important because it confers multidrug resistance. The homologous halves of P-gp each contain a transmembrane (TM) domain (TMD) with 6 TM segments followed by a nucleotide-binding domain (NBD). The drug- and ATP-binding sites reside at the interface between the TMDs and NBDs, respectively. Each NBD is connected to the TMDs by a transmission interface involving a pair of intracellular loops (ICLs) that form ball-and-socket joints. P-gp is different from CFTR (ABCC7) in that deleting NBD2 causes misprocessing of only P-gp. Therefore, NBD2 might be critical for stabilizing ICLs 2 and 3 that form a tetrahelix bundle at the NBD2 interface. Here we report that the NBD1 and NBD2 transmission interfaces in P-gp are asymmetric. Point mutations to 25 of 60 ICL2/ICL3 residues at the NBD2 transmission interface severely reduced P-gp assembly while changes to the equivalent residues in ICL1/ICL4 at the NBD1 interface had little effect. The hydrophobic nature at the transmission interfaces was also different. Mutation of Phe-1086 or Tyr-1087 to arginine at the NBD2 socket blocked activity or assembly while the equivalent mutations at the NBD1 socket had only modest effects. The results suggest that the NBD transmission interfaces are asymmetric. In contrast to the ICL2/3-NBD2 interface, the ICL1/4-NBD1 transmission interface is more hydrophilic and insensitive to mutations. Therefore the ICL2/3-NBD2 transmission interface forms a precise hydrophobic connection that acts as a linchpin for assembly and trafficking of P-gp.
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No. Sentence Comment
200 The Y444A and Y444L mutants yielded about 25% mature P-gp while the Y444R mutant yielded about 40% mature P-gp (Fig. 4A).
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ABCB1 p.Tyr444Arg 25987565:200:68
status: NEW207 Both the Y444F and Y444R mutants showed over 75% of wild-type activity.
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ABCB1 p.Tyr444Arg 25987565:207:19
status: NEW212 The L443R and Y444R mutations only showed modest reductions (Fig. 4).
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ABCB1 p.Tyr444Arg 25987565:212:14
status: NEW276 The F1086R or Y1087R mutations at the NBD2 socket blocked maturation and activity while P-gp showed substantial activity when the comparable mutations (L443R, Y444R) were made to the NBD1 socket.
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ABCB1 p.Tyr444Arg 25987565:276:159
status: NEW