8RGL

Structure of Human Serum Albumin in complex with Aristolochic Acid I at 1.9 A resolution - Optimized

Replaces:  7OV6

Summary for 8RGL

• Entry DOI: 10.2210/pdb8rgl/pdb
• Related: 8RCO 8RCP 8RGK
• Descriptor: Serum albumin, MYRISTIC ACID, 1,2-ETHANEDIOL, ... (5 entities in total)
• Functional Keywords: human serum albumin, hsa, aristolochic acid i, aai, transport protein
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 142424.45

Authors

Pomyalov, S.,Sidorenko, V.S.,Grollman, A.P.,Shoham, G. (deposition date: 2023-12-13, release date: 2024-06-26, Last modification date: 2024-11-06)

Primary citation

Pomyalov, S.,Minetti, C.A.,Remeta, D.P.,Bonala, R.,Johnson, F.,Zaitseva, I.,Iden, C.,Golebiewska, U.,Breslauer, K.J.,Shoham, G.,Sidorenko, V.S.,Grollman, A.P.
Structural and mechanistic insights into the transport of aristolochic acids and their active metabolites by human serum albumin.
J.Biol.Chem., 300:107358-107358, 2024

PubMed Abstract: Aristolochic acids I and II (AA-I/II) are carcinogenic principles of Aristolochia plants, which have been employed in traditional medicinal practices and discovered as food contaminants. While the deleterious effects of AAs are broadly acknowledged, there is a dearth of information to define the mechanisms underlying their carcinogenicity. Following bioactivation in the liver, N-hydroxyaristolactam and N-sulfonyloxyaristolactam metabolites are transported via circulation and elicit carcinogenic effects by reacting with cellular DNA. In this study, we apply DNA adduct analysis, X-ray crystallography, isothermal titration calorimetry, and fluorescence quenching to investigate the role of human serum albumin (HSA) in modulating AA carcinogenicity. We find that HSA extends the half-life and reactivity of N-sulfonyloxyaristolactam-I with DNA, thereby protecting activated AAs from heterolysis. Applying novel pooled plasma HSA crystallization methods, we report high-resolution structures of myristic acid-enriched HSA (HSA) and its AA complexes (HSA/AA-I and HSA/AA-II) at 1.9 Å resolution. While AA-I is located within HSA subdomain IB, AA-II occupies subdomains IIA and IB. ITC binding profiles reveal two distinct AA sites in both complexes with association constants of 1.5 and 0.5 · 10 M for HSA/AA-I versus 8.4 and 9.0 · 10 M for HSA/AA-II. Fluorescence quenching of the HSA Trp suggests variable impacts of fatty acids on ligand binding affinities. Collectively, our structural and thermodynamic characterizations yield significant insights into AA binding, transport, toxicity, and potential allostery, critical determinants for elucidating the mechanistic roles of HSA in modulating AA carcinogenicity.

PubMed: 38782206
DOI: 10.1016/j.jbc.2024.107358

Experimental method

X-RAY DIFFRACTION (1.9 Å)