Terazosin activates Pgk1 and Hsp90 to promote stress resistance.
Drugs that can protect against organ damage are urgently needed, especially for diseases such as sepsis and brain stroke. We discovered that terazosin (TZ), a widely marketed α1-adrenergic receptor antagonist, alleviated organ damage and improved survival in rodent models of stroke and sepsis. Through combined studies of enzymology and X-ray crystallography, we discovered that TZ binds a new target, phosphoglycerate kinase 1 (Pgk1), and activates its enzymatic activity, probably through 2,4-diamino-6,7-dimethoxyisoquinoline's ability to promote ATP release from Pgk1. Mechanistically, the ATP generated from Pgk1 may enhance the chaperone activity of Hsp90, an ATPase known to associate with Pgk1. Upon activation, Hsp90 promotes multistress resistance. Our studies demonstrate that TZ has a new protein target, Pgk1, and reveal its corresponding biological effect. As a clinical drug, TZ may be quickly translated into treatments for diseases including stroke and sepsis.
1] State Key Laboratory of Biomembrane and Membrane Biotechnology, School of Life Sciences, Peking University, Beijing, China. [2] Beijing Institute for Brain Disorder and Beijing Tiantan Hospital, Capital Medical University, Beijing, China.
Xinping
X
Chen
1] State Key Laboratory of Biomembrane and Membrane Biotechnology, School of Life Sciences, Peking University, Beijing, China. [2] Beijing Institute for Brain Disorder and Beijing Tiantan Hospital, Capital Medical University, Beijing, China.
Chunyue
0000000308897871
C
Zhao
1] School of Life Sciences, University of Science and Technology of China, Hefei, China. [2] School of Life Science, Peking University, Beijing, China.
Xiaolong
X
Li
1] State Key Laboratory of Biomembrane and Membrane Biotechnology, School of Life Sciences, Peking University, Beijing, China. [2] Beijing Institute for Brain Disorder and Beijing Tiantan Hospital, Capital Medical University, Beijing, China.
Tao
T
Wang
Key Laboratory of Bioorganic Chemistry and Molecular Engineering, College of Chemistry and Molecular Engineering, Peking University, Beijing, China.
Yizhou
Y
Li
Key Laboratory of Bioorganic Chemistry and Molecular Engineering, College of Chemistry and Molecular Engineering, Peking University, Beijing, China.
Cheng
C
Cao
National Institute of Biological Sciences, Beijing, China.
Yuehe
Y
Ding
National Institute of Biological Sciences, Beijing, China.
Mengqiu
M
Dong
School of Life Science, Peking University, Beijing, China.
Lorenzo
L
Finci
1] School of Life Sciences, University of Science and Technology of China, Hefei, China. [2] School of Life Science, Peking University, Beijing, China. [3] Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.
Jia-Huai
JH
Wang
1] Key Laboratory of Bioorganic Chemistry and Molecular Engineering, College of Chemistry and Molecular Engineering, Peking University, Beijing, China. [2] Key Laboratory of Chemical Genomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen, China.
Xiaoyu
X
Li
Beijing Institute for Brain Disorder and Beijing Tiantan Hospital, Capital Medical University, Beijing, China.
Lei
L
Liu
D058668:Adrenergic alpha-1 Receptor Antagonists / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D018841:HSP90 Heat-Shock Proteins / Q000737:chemistry / Q000187:drug effects*; D020244:Infarction, Middle Cerebral Artery / Q000188:drug therapy / Q000473:pathology; D051379:Mice; D008958:Models, Molecular; D010735:Phosphoglycerate Kinase / Q000737:chemistry / Q000187:drug effects*; D011224:Prazosin / Q000031:analogs & derivatives* / Q000494:pharmacology; D011487:Protein Conformation; D051381:Rats; D018805:Sepsis / Q000188:drug therapy; D013312:Stress, Physiological / Q000187:drug effects*; D020521:Stroke / Q000188:drug therapy
D058668:Adrenergic alpha-1 Receptor Antagonists; D016207:Cytokines; D018841:HSP90 Heat-Shock Proteins; C041226:Terazosin; C528165:Pgk1 protein, mouse; D010735:Phosphoglycerate Kinase; D011224:Prazosin