2007 Fiscal Year Final Research Report Summary
Mapping of drug binding sites on al-acid glycoprotein
| Project/Area Number |
18590035
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Physical pharmacy
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| Research Institution | Kumamoto University |
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Principal Investigator |
MARUYAMA Toru Kumamoto University, Faculty of Pharmaceutical Sciences, Professor (90423657)
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| Co-Investigator(Kenkyū-buntansha) |
OTAGIRI Masaki Kumamoto University, Faculty of Medical and Pharmaceutical Sciences, Professor (80120145)
KAWAHARA Koichi Kumamoto University, Faculty of Medical and Pharmaceutical Sciences, Research associate (10347015)
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| Project Period (FY) |
2006 – 2007
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| Keywords | biochemistry / nrotein binding / al-acid elvconrotein |
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| Research Abstract |
There are at least two genetic variants of human al-acid glycoprotein (AGP) (the A and F1*S variants)that are encoded by two different genes. AGP is a major carrier of basic drugs in circulation and the variants of AGP have different drug-binding properties. The purpose of this study was to identify the amino acid residues that are responsible for the selectivity of drug binding to genetic variants of AGP using site-directed mutagenesis. First, we screened amino acid residues in the region proximal to position 100 that are involved in binding of warfarin and dipyridamole, which are F1*S-specific ligands, and of propafenone, which is an A-specific ligand, using ultrafiltration. In the F1*S variant, His97 and His100 were involved in warfarin- and dipyridamole-binding, respectively; Trp122 also contributed to binding of both ligands. G1u92, His100 and Trp 122 participated in the binding of propafenone in the A variant. Exchange of the residue at position 92 between AGP variants reversed the relative strength of propafenone binding to the two variants but had a markedly di8erent effect on binding of warfarin and dipyridamole. The V92E mutation decreased warfarin binding to the Fl*S variant, while the E92V mutation increased dipyridamole binding to the A variant; although, both drugs had greater binding affinities for the wild-type F1*S variant than for either mutant. These findings indicate that the amino acid residue at position 92 plays a significant role in drug-binding selectivity in AGP variants, especially for drugs that preferentially bind to the A variant.
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