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Crystallographic analysis reveals the structural basis of the high-affinity binding of iophenoxic acid to human serum albumin.

Ryan AJ, Chung CW, Curry S - BMC Struct. Biol. (2011)

Bottom Line: It was replaced by Iopanoic acid, which has an amino rather than a hydroxyl group at position 3 on the iodinated benzyl ring and, as a result, binds to albumin with lower affinity and is excreted more rapidly from the body.Consistent with this interpretation, the structure also suggests that the lower-affinity binding of iopanoic acid arises because replacement of the 3-hydroxyl by an amino group eliminates hydrogen bonding to Arg 257.This finding underscores the importance of polar interactions in high-affinity binding to albumin.

View Article: PubMed Central - HTML - PubMed

Affiliation: Biophysics Section, Blackett Laboratory, Imperial College, Exhibition Road, London, SW7 2AZ, UK.

ABSTRACT

Background: Iophenoxic acid is an iodinated radiocontrast agent that was withdrawn from clinical use because of its exceptionally long half-life in the body, which was due in part to its high-affinity binding to human serum albumin (HSA). It was replaced by Iopanoic acid, which has an amino rather than a hydroxyl group at position 3 on the iodinated benzyl ring and, as a result, binds to albumin with lower affinity and is excreted more rapidly from the body. To understand how iophenoxic acid binds so tightly to albumin, we wanted to examine the structural basis of its interaction with HSA.

Results: We have determined the co-crystal structure of HSA in complex with iophenoxic acid at 2.75 Å resolution, revealing a total of four binding sites, two of which--in drugs sites 1 and 2 on the protein--are likely to be occupied at clinical doses. High-affinity binding of iophenoxic acid occurs at drug site 1. The structure reveals that polar and apolar groups on the compound are involved in its interactions with drug site 1. In particular, the 3-hydroxyl group makes three hydrogen bonds with the side-chains of Tyr 150 and Arg 257. The mode of binding to drug site 2 is similar except for the absence of a binding partner for the hydroxyl group on the benzyl ring of the compound.

Conclusions: The HSA-iophenoxic acid structure indicates that high-affinity binding to drug site 1 is likely to be due to extensive desolvation of the compound, coupled with the ability of the binding pocket to provide a full set of salt-bridging or hydrogen bonding partners for its polar groups. Consistent with this interpretation, the structure also suggests that the lower-affinity binding of iopanoic acid arises because replacement of the 3-hydroxyl by an amino group eliminates hydrogen bonding to Arg 257. This finding underscores the importance of polar interactions in high-affinity binding to albumin.

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Comparative binding of iophenoxic acid and other ligands to drug site 1 of HSA. (a) Superposition of iophenoxic acid and warfarin [23]. Y150 is omitted from this figure to improve the visibility of the ligands. (b) Superposition of iophenoxic and other iodinated compounds that bind to drug site 1, including iodipamide (iod), tri-iodobenzoic acid (tib), di-iodosalicylic acid (dis) and thyroxine (trx) [10,24,30].
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Figure 3: Comparative binding of iophenoxic acid and other ligands to drug site 1 of HSA. (a) Superposition of iophenoxic acid and warfarin [23]. Y150 is omitted from this figure to improve the visibility of the ligands. (b) Superposition of iophenoxic and other iodinated compounds that bind to drug site 1, including iodipamide (iod), tri-iodobenzoic acid (tib), di-iodosalicylic acid (dis) and thyroxine (trx) [10,24,30].

Mentions: Iophenoxic acid fits snugly into the main chamber of drug site 1 where, with the exception of the carboxylate group, it is entirely shielded from solvent (Figure 2c). As observed for many other aromatic compounds [10,23], the centre of the tri-iodinated ring is contacted on either side by the side-chains of Leu 238 and Ala 291 (Figure 3a). In particular, it is worth noting that the radiocontrast agent binds is a similar position and orientation to other compounds that are composed primarily of iodinated aromatic rings, such as tri-iodobenzoic acid, di-iodosalicylic acid and iodipamide [10,24] (Figure 3b); for all three compounds there is a common locus for at least two iodine atoms (three in the case of iodipamide).


Crystallographic analysis reveals the structural basis of the high-affinity binding of iophenoxic acid to human serum albumin.

Ryan AJ, Chung CW, Curry S - BMC Struct. Biol. (2011)

Comparative binding of iophenoxic acid and other ligands to drug site 1 of HSA. (a) Superposition of iophenoxic acid and warfarin [23]. Y150 is omitted from this figure to improve the visibility of the ligands. (b) Superposition of iophenoxic and other iodinated compounds that bind to drug site 1, including iodipamide (iod), tri-iodobenzoic acid (tib), di-iodosalicylic acid (dis) and thyroxine (trx) [10,24,30].
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3104944&req=5

Figure 3: Comparative binding of iophenoxic acid and other ligands to drug site 1 of HSA. (a) Superposition of iophenoxic acid and warfarin [23]. Y150 is omitted from this figure to improve the visibility of the ligands. (b) Superposition of iophenoxic and other iodinated compounds that bind to drug site 1, including iodipamide (iod), tri-iodobenzoic acid (tib), di-iodosalicylic acid (dis) and thyroxine (trx) [10,24,30].
Mentions: Iophenoxic acid fits snugly into the main chamber of drug site 1 where, with the exception of the carboxylate group, it is entirely shielded from solvent (Figure 2c). As observed for many other aromatic compounds [10,23], the centre of the tri-iodinated ring is contacted on either side by the side-chains of Leu 238 and Ala 291 (Figure 3a). In particular, it is worth noting that the radiocontrast agent binds is a similar position and orientation to other compounds that are composed primarily of iodinated aromatic rings, such as tri-iodobenzoic acid, di-iodosalicylic acid and iodipamide [10,24] (Figure 3b); for all three compounds there is a common locus for at least two iodine atoms (three in the case of iodipamide).

Bottom Line: It was replaced by Iopanoic acid, which has an amino rather than a hydroxyl group at position 3 on the iodinated benzyl ring and, as a result, binds to albumin with lower affinity and is excreted more rapidly from the body.Consistent with this interpretation, the structure also suggests that the lower-affinity binding of iopanoic acid arises because replacement of the 3-hydroxyl by an amino group eliminates hydrogen bonding to Arg 257.This finding underscores the importance of polar interactions in high-affinity binding to albumin.

View Article: PubMed Central - HTML - PubMed

Affiliation: Biophysics Section, Blackett Laboratory, Imperial College, Exhibition Road, London, SW7 2AZ, UK.

ABSTRACT

Background: Iophenoxic acid is an iodinated radiocontrast agent that was withdrawn from clinical use because of its exceptionally long half-life in the body, which was due in part to its high-affinity binding to human serum albumin (HSA). It was replaced by Iopanoic acid, which has an amino rather than a hydroxyl group at position 3 on the iodinated benzyl ring and, as a result, binds to albumin with lower affinity and is excreted more rapidly from the body. To understand how iophenoxic acid binds so tightly to albumin, we wanted to examine the structural basis of its interaction with HSA.

Results: We have determined the co-crystal structure of HSA in complex with iophenoxic acid at 2.75 Å resolution, revealing a total of four binding sites, two of which--in drugs sites 1 and 2 on the protein--are likely to be occupied at clinical doses. High-affinity binding of iophenoxic acid occurs at drug site 1. The structure reveals that polar and apolar groups on the compound are involved in its interactions with drug site 1. In particular, the 3-hydroxyl group makes three hydrogen bonds with the side-chains of Tyr 150 and Arg 257. The mode of binding to drug site 2 is similar except for the absence of a binding partner for the hydroxyl group on the benzyl ring of the compound.

Conclusions: The HSA-iophenoxic acid structure indicates that high-affinity binding to drug site 1 is likely to be due to extensive desolvation of the compound, coupled with the ability of the binding pocket to provide a full set of salt-bridging or hydrogen bonding partners for its polar groups. Consistent with this interpretation, the structure also suggests that the lower-affinity binding of iopanoic acid arises because replacement of the 3-hydroxyl by an amino group eliminates hydrogen bonding to Arg 257. This finding underscores the importance of polar interactions in high-affinity binding to albumin.

Show MeSH
Related in: MedlinePlus