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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Background: Iophenoxic acid is an iodinated radiocontrast agent that was withdrawn from clinical use because of its exceptionally long half-life in the body, which was due in part to its high-affinity binding to human serum albumin (HSA).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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Structural details of iophenoxic acid bound to drug site 2 in sub-domain IIIA. (a) Close-up of iophenoxic acid bound in drug site 2, using the same representation of features as in Figure 2c). (b) Superposition of iophenoxic acid and diazepam (dzp) [10]. The side-chain conformations of L387 and L453 in the HSA-diazepam complex are shown as dark-grey sticks.
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Figure 4: Structural details of iophenoxic acid bound to drug site 2 in sub-domain IIIA. (a) Close-up of iophenoxic acid bound in drug site 2, using the same representation of features as in Figure 2c). (b) Superposition of iophenoxic acid and diazepam (dzp) [10]. The side-chain conformations of L387 and L453 in the HSA-diazepam complex are shown as dark-grey sticks.

Mentions: There are many similarities in the binding of iophenoxic acid to drug sites 1 and 2. In drug site 2 the compound is completely enclosed except for the partial exposure of the carboxylate at the pocket entrance, where it makes specific interactions -- though in this case they are hydrogen bonds, not salt-bridges -- with the side-chains of Tyr 411 and Ser 489 (Figure 4a). The hydroxyl group is again positioned deep within the pocket but, although it is in the vicinity of the backbone carbonyl of Leu 430 [10], it is too far away (4.4 Å) to make a hydrogen bond interaction. In contrast to the smaller propofol molecule (see Figure 2 of ref [25]), the steric hindrance caused by the three bulky iodine atoms prevents iophenoxic acid from rotating to a position that would allow the hydroxyl group to form a hydrogen bond with this group.


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)

Structural details of iophenoxic acid bound to drug site 2 in sub-domain IIIA. (a) Close-up of iophenoxic acid bound in drug site 2, using the same representation of features as in Figure 2c). (b) Superposition of iophenoxic acid and diazepam (dzp) [10]. The side-chain conformations of L387 and L453 in the HSA-diazepam complex are shown as dark-grey sticks.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 4: Structural details of iophenoxic acid bound to drug site 2 in sub-domain IIIA. (a) Close-up of iophenoxic acid bound in drug site 2, using the same representation of features as in Figure 2c). (b) Superposition of iophenoxic acid and diazepam (dzp) [10]. The side-chain conformations of L387 and L453 in the HSA-diazepam complex are shown as dark-grey sticks.
Mentions: There are many similarities in the binding of iophenoxic acid to drug sites 1 and 2. In drug site 2 the compound is completely enclosed except for the partial exposure of the carboxylate at the pocket entrance, where it makes specific interactions -- though in this case they are hydrogen bonds, not salt-bridges -- with the side-chains of Tyr 411 and Ser 489 (Figure 4a). The hydroxyl group is again positioned deep within the pocket but, although it is in the vicinity of the backbone carbonyl of Leu 430 [10], it is too far away (4.4 Å) to make a hydrogen bond interaction. In contrast to the smaller propofol molecule (see Figure 2 of ref [25]), the steric hindrance caused by the three bulky iodine atoms prevents iophenoxic acid from rotating to a position that would allow the hydroxyl group to form a hydrogen bond with this group.

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