6WUW

Crystal structure of Human Serum Albumin complex with JMS-053

Summary for 6WUW

• Entry DOI: 10.2210/pdb6wuw/pdb
• Descriptor: Serum albumin, MYRISTIC ACID, 7-imino-2-phenylthieno[3,2-c]pyridine-4,6(5H,7H)-dione, ... (8 entities in total)
• Functional Keywords: albumin, hsa, drug transport, jms-053, structural genomics, center for structural genomics of infectious diseases, csgid, transport protein
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 136967.83

Authors

Czub, M.P.,Cooper, D.R.,Shabalin, I.G.,Lazo, J.S.,Minor, W.,Center for Structural Genomics of Infectious Diseases (CSGID) (deposition date: 2020-05-05, release date: 2020-05-20, Last modification date: 2024-10-30)

Primary citation

Czub, M.P.,Boulton, A.M.,Rastelli, E.J.,Tasker, N.R.,Maskrey, T.S.,Blanco, I.K.,McQueeney, K.E.,Bushweller, J.H.,Minor, W.,Wipf, P.,Sharlow, E.R.,Lazo, J.S.
Structure of the Complex of an Iminopyridinedione Protein Tyrosine Phosphatase 4A3 Phosphatase Inhibitor with Human Serum Albumin.
Mol.Pharmacol., 98:648-657, 2020

PubMed Abstract: 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-]pyridine-4,6(5,7)-dione), has a long plasma half-life (∼ 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.

PubMed: 32978326
DOI: 10.1124/molpharm.120.000131

Experimental method

X-RAY DIFFRACTION (2.2 Å)