A new drug binding subsite on human serum albumin and drug-drug interaction studied by X-ray crystallography.
3'-Azido-3'-deoxythymidine (AZT) is the first clinically effective drug for the treatment of human immunodeficiency virus infection. The drug interaction with human serum albumin (HSA) has been an important component in understanding its mechanism of action, especially in drug distribution and in drug-drug interaction on HSA in the case of multi-drug therapy. We present here crystal structures of a ternary HSA-Myr-AZT complex and a quaternary HSA-Myr-AZT-SAL complex (Myr, myristate; SAL, salicylic acid). From this study, a new drug binding subsite on HSA Sudlow site 1 was identified. The presence of fatty acid is needed for the creation of this subsite due to fatty acid induced conformational changes of HSA. Thus, the Sudlow site 1 of HSA can be divided into three non-overlapped subsites: a SAL subsite, an indomethacin subsite and an AZT subsite. Binding of a drug to HSA often influences simultaneous binding of other drugs. From the HSA-Myr-AZT-SAL complex structure, we observed the coexistence of two drugs (AZT and SAL) in Sudlow site 1 and the competition between these two drugs in subdomain IB. These results provide new structural information on HSA-drug interaction and drug-drug interaction on HSA.
Zhu
Lili
L
State Key Laboratory of Structural Chemistry, Fujian Institute of Research on the Structure of Matter, The Chinese Academy of Sciences, 155 Yang Qiao Xi Lu, Fuzhou, Fujian 350002, China. zhulili@fjirsm.ac.cn
Yang
Feng
F
Chen
Liqing
L
Meehan
Edward J
EJ
Huang
Mingdong
M
D001665:Binding Sites; D018360:Crystallography, X-Ray / Q000379:methods; D004347:Drug Interactions; D006801:Humans; D008958:Models, Molecular; D011485:Protein Binding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D020156:Salicylic Acid / Q000737:chemistry / Q000378:metabolism; D012709:Serum Albumin / Q000737:chemistry* / Q000378:metabolism*; D015215:Zidovudine / Q000737:chemistry / Q000378:metabolism
D012709:Serum Albumin; D015215:Zidovudine; D020156:Salicylic Acid