| Structural highlights
6wuw is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Ligands: | , , , , , |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Disease
[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.[1] [2] [3] [4]
Function
[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.[5]
Publication Abstract from PubMed
Protein tyrosine phosphatase (PTP) 4A3 is frequently overexpressed in human solid tumors and hematologic malignancies and is associated with tumor cell invasion, metastasis, and a poor patient prognosis. Several potent, selective, and allosteric small molecule inhibitors of PTP4A3 were recently identified. A lead compound in the series, JMS-053 (7-imino-2-phenylthieno[3,2-c]pyridine-4,6(5H,7H)-dione), has a long plasma half-life ( approximately 24 hours) in mice, suggesting possible binding to serum components. We confirmed by isothermal titration calorimetry that JMS-053 binds to human serum albumin. A single JMS-053 binding site was identified by X-ray crystallography in human serum albumin at drug site 3, which is also known as subdomain IB. The binding of JMS-053 to human serum albumin, however, did not markedly alter the overall albumin structure. In the presence of serum albumin, the potency of JMS-053 as an in vitro inhibitor of PTP4A3 and human A2780 ovarian cancer cell growth was reduced. The reversible binding of JMS-053 to serum albumin may serve to increase JMS-053's plasma half-life and thus extend the delivery of the compound to tumors. SIGNIFICANCE STATEMENT: X-ray crystallography revealed that a potent, reversible, first-in-class small molecule inhibitor of the oncogenic phosphatase protein tyrosine phosphatase 4A3 binds to at least one site on human serum albumin, which is likely to extend the compound's plasma half-life and thus assist in drug delivery into tumors.
Structure of the Complex of an Iminopyridinedione Protein Tyrosine Phosphatase 4A3 Phosphatase Inhibitor with Human Serum Albumin.,Czub MP, Boulton AM, Rastelli EJ, Tasker NR, Maskrey TS, Blanco IK, McQueeney KE, Bushweller JH, Minor W, Wipf P, Sharlow ER, Lazo JS Mol Pharmacol. 2020 Dec;98(6):648-657. doi: 10.1124/molpharm.120.000131. Epub, 2020 Sep 25. PMID:32978326[6]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ 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
- ↑ Czub MP, Boulton AM, Rastelli EJ, Tasker NR, Maskrey TS, Blanco IK, McQueeney KE, Bushweller JH, Minor W, Wipf P, Sharlow ER, Lazo JS. Structure of the Complex of an Iminopyridinedione Protein Tyrosine Phosphatase 4A3 Phosphatase Inhibitor with Human Serum Albumin. Mol Pharmacol. 2020 Dec;98(6):648-657. doi: 10.1124/molpharm.120.000131. Epub, 2020 Sep 25. PMID:32978326 doi:http://dx.doi.org/10.1124/molpharm.120.000131
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