7WKZ

Crystal structure of the HSA complex with mycophenolate and aripiprazole

Summary for 7WKZ

• Entry DOI: 10.2210/pdb7wkz/pdb
• Descriptor: Serum albumin, 7-[4-[4-[2,3-bis(chloranyl)phenyl]piperazin-1-yl]butoxy]-3,4-dihydro-1H-quinolin-2-one, MYCOPHENOLIC ACID (3 entities in total)
• Functional Keywords: drug, complex, transport protein
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 134679.88

Authors

Kawai, A.,Yamasaki, K. (deposition date: 2022-01-12, release date: 2022-12-28, Last modification date: 2024-11-06)

Primary citation

Yamasaki, K.,Teshima, H.,Yukizawa, R.,Kuyama, K.,Tsukigawa, K.,Nishi, K.,Otagiri, M.,Kawai, A.
Structural Basis of the Change in the Interaction Between Mycophenolic Acid and Subdomain IIA of Human Serum Albumin During Renal Failure.
J.Med.Chem., 66:951-961, 2023

PubMed Abstract: Mycophenolic acid (MP) is an active metabolite of mycophenolate mofetil, a widely used immunosuppressive drug. MP normally exhibits high plasma protein binding (97-99%), but its binding rate is decreased in patients with renal insufficiency. This decreased protein binding is thought to be associated with leukopenia, a side effect of MP. In this study, we characterized the change in protein binding of MP in renal failure patients. Our findings indicate that MP binds strongly to subdomain IIA of human serum albumin. X-ray crystallographic data indicated that the isobenzofuran group of MP forms a stacking interaction with Trp214, and the carboxyl group of MP is located at a position that allows the formation of hydrogen bonds with Tyr150, His242, or Arg257. Due to the specific binding of MP to subdomain IIA, MP is thought to be displaced by uremic toxin (3-carboxy-4-methyl-5-propyl-2-furan-propionic acid) and fatty acids (oleate or myristate) that can bind to subdomain IIA, resulting in the decreased plasma protein binding of MP in renal failure.

PubMed: 36538495
DOI: 10.1021/acs.jmedchem.2c01790

Experimental method

X-RAY DIFFRACTION (2.992 Å)