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|2ydf, resolution 2.75Å ()|
|Related:|| 2bxq, 1hk4, 2xvu, 2bxi, 2vuf, 2xvv, 1o9x, 1bke, 2bxk, 1hk1, 1uor, 1h9z, 1e7b, 1hk2, 1hk5, 2esg, 1e7e, 2xvq, 2bxg, 2bxh, 2bxo, 2bxf, 1ysx, 1e7g, 1ao6, 2bxc, 2bxe, 1tf0, 2bxn, 1e7c, 1gnj, 2xw0, 1e7h, 2bxa, 1hk3, 2xsi, 2xvw, 2bxb, 2xw1, 1e7i, 2bxl, 1gni, 1ha2, 1bj5, 1e7a, 2bxp, 2bxd, 1bm0, 1e78, 2vdb, 1e7f, 1n5u, 2bxm, 2bx8, 2vue
HUMAN SERUM ALBUMIN COMPLEXED WITH IOPHENOXIC ACID
ABSTRACT: BACKGROUND: Iophenoxic acid is an iodinated radiocontrast agent that was withdrawn from clinical use because of its exceptionally long half-life in the body, which was due in part to its high-affinity binding to human serum albumin (HSA).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 A 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.
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 Apr 18;11(1):18. PMID:21501503
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
[ALBU_HUMAN] Defects in ALB are a cause of familial dysalbuminemic hyperthyroxinemia (FDH) [MIM:103600]. FDH is a form of euthyroid hyperthyroxinemia that is due to increased affinity of ALB for T(4). It is the most common cause of inherited euthyroid hyperthyroxinemia in Caucasian population.
[ALBU_HUMAN] Serum albumin, the main protein of plasma, has a good binding capacity for water, Ca(2+), Na(+), K(+), fatty acids, hormones, bilirubin and drugs. Its main function is the regulation of the colloidal osmotic pressure of blood. Major zinc transporter in plasma, typically binds about 80% of all plasma zinc.
About this Structure
- Ryan AJ, Chung CW, Curry S. Crystallographic analysis reveals the structural basis of the high-affinity binding of Iophenoxic acid to Human Serum Albumin. BMC Struct Biol. 2011 Apr 18;11(1):18. PMID:21501503 doi:10.1186/1472-6807-11-18
- ↑ Sunthornthepvarakul T, Angkeow P, Weiss RE, Hayashi Y, Refetoff S. An identical missense mutation in the albumin gene results in familial dysalbuminemic hyperthyroxinemia in 8 unrelated families. Biochem Biophys Res Commun. 1994 Jul 29;202(2):781-7. PMID:8048949
- ↑ Rushbrook JI, Becker E, Schussler GC, Divino CM. Identification of a human serum albumin species associated with familial dysalbuminemic hyperthyroxinemia. J Clin Endocrinol Metab. 1995 Feb;80(2):461-7. PMID:7852505
- ↑ Wada N, Chiba H, Shimizu C, Kijima H, Kubo M, Koike T. A novel missense mutation in codon 218 of the albumin gene in a distinct phenotype of familial dysalbuminemic hyperthyroxinemia in a Japanese kindred. J Clin Endocrinol Metab. 1997 Oct;82(10):3246-50. PMID:9329347
- ↑ Sunthornthepvarakul T, Likitmaskul S, Ngowngarmratana S, Angsusingha K, Kitvitayasak S, Scherberg NH, Refetoff S. Familial dysalbuminemic hypertriiodothyroninemia: a new, dominantly inherited albumin defect. J Clin Endocrinol Metab. 1998 May;83(5):1448-54. PMID:9589637
- ↑ Lu J, Stewart AJ, Sadler PJ, Pinheiro TJ, Blindauer CA. Albumin as a zinc carrier: properties of its high-affinity zinc-binding site. Biochem Soc Trans. 2008 Dec;36(Pt 6):1317-21. doi: 10.1042/BST0361317. PMID:19021548 doi:10.1042/BST0361317