1HK3

Human serum albumin mutant r218p complexed with thyroxine (3,3',5,5'-tetraiodo-l-thyronine)

Summary for 1HK3

• Entry DOI: 10.2210/pdb1hk3/pdb
• Related: 1AO6 1BJ5 1BKE 1BM0 1E78 1E7A 1E7B 1E7C 1E7E 1E7F 1E7G 1E7H 1E7I 1GNI 1GNJ 1H9Z 1HA2 1HK1 1HK2 1HK4 1HK5 1O9X 1UOR
• Descriptor: SERUM ALBUMIN, 3,5,3',5'-TETRAIODO-L-THYRONINE (3 entities in total)
• Functional Keywords: plasma protein, hormone-binding, lipid-binding, thyroxine, familial dysalbuminemic hyperthyroxinemia
• Biological source: HOMO SAPIENS (HUMAN)
• Total number of polymer chains: 1
• Total formula weight: 69618.62

Authors

Petitpas, I.,Petersen, C.E.,Ha, C.E.,Bhattacharya, A.A.,Zunszain, P.A.,Ghuman, J.,Bhagavan, N.V.,Curry, S. (deposition date: 2003-03-05, release date: 2003-05-16, Last modification date: 2023-12-13)

Primary citation

Petitpas, I.,Petersen, C.E.,Ha, C.E.,Bhattacharya, A.A.,Zunszain, P.A.,Ghuman, J.,Bhagavan, N.V.,Curry, S.
Structural Basis of Albumin-Thyroxine Interactions and Familial Dysalbuminemic Hyperthyroxinemia
Proc.Natl.Acad.Sci.USA, 100:6440-, 2003

PubMed Abstract: Human serum albumin (HSA) is the major protein component of blood plasma and serves as a transporter for thyroxine and other hydrophobic compounds such as fatty acids and bilirubin. We report here a structural characterization of HSA-thyroxine interactions. Using crystallographic analyses we have identified four binding sites for thyroxine on HSA distributed in subdomains IIA, IIIA, and IIIB. Mutation of residue R218 within subdomain IIA greatly enhances the affinity for thyroxine and causes the elevated serum thyroxine levels associated with familial dysalbuminemic hyperthyroxinemia (FDH). Structural analysis of two FDH mutants of HSA (R218H and R218P) shows that this effect arises because substitution of R218, which contacts the hormone bound in subdomain IIA, produces localized conformational changes to relax steric restrictions on thyroxine binding at this site. We have also found that, although fatty acid binding competes with thyroxine at all four sites, it induces conformational changes that create a fifth hormone-binding site in the cleft between domains I and III, at least 9 A from R218. These structural observations are consistent with binding data showing that HSA retains a high-affinity site for thyroxine in the presence of excess fatty acid that is insensitive to FDH mutations.

PubMed: 12743361
DOI: 10.1073/PNAS.1137188100

Experimental method

X-RAY DIFFRACTION (2.8 Å)