TY - JOUR
T1 - Structural basis of antagonizing the vitamin K catalytic cycle for anticoagulation
AU - Liu, Shixuan
AU - Li, Shuang
AU - Shen, Guomin
AU - Sukumar, Narayanasami
AU - Krezel, Andrzej M.
AU - Li, Weikai
N1 - Funding Information:
W.L. is supported by National Heart, Lung, and Blood Institute (NHLBI) (R01 HL121718), W. M. Keck Foundation (Forefront of Science Award), Children's Discovery Institute (MCII 2020-854), National Eye Institute (NEI) (R21 EY028705), and National Institute of General Medical Sciences (NIGMS) (R01 GM131008). The NECAT beamlines are funded by NIGMS (P30 GM124165), the Eiger detector is funded by a NIH-ORIP (HEI S10OD021527), and APS is supported by the U.S. Department of Energy (DOE) (DE-AC02-06CH11357).
Publisher Copyright:
© 2021 American Association for the Advancement of Science. All rights reserved.
PY - 2021/1/1
Y1 - 2021/1/1
N2 - Vitamin K antagonists are widely used anticoagulants that target vitamin K epoxide reductases (VKOR), a family of integral membrane enzymes. To elucidate their catalytic cycle and inhibitory mechanism, we report 11 x-ray crystal structures of human VKOR and pufferfish VKOR-like, with substrates and antagonists in different redox states. Substrates entering the active site in a partially oxidized state form cysteine adducts that induce an open-to-closed conformational change, triggering reduction. Binding and catalysis are facilitated by hydrogen-bonding interactions in a hydrophobic pocket. The antagonists bind specifically to the same hydrogenbonding residues and induce a similar closed conformation. Thus, vitamin K antagonists act through mimicking the key interactions and conformational changes required for the VKOR catalytic cycle.
AB - Vitamin K antagonists are widely used anticoagulants that target vitamin K epoxide reductases (VKOR), a family of integral membrane enzymes. To elucidate their catalytic cycle and inhibitory mechanism, we report 11 x-ray crystal structures of human VKOR and pufferfish VKOR-like, with substrates and antagonists in different redox states. Substrates entering the active site in a partially oxidized state form cysteine adducts that induce an open-to-closed conformational change, triggering reduction. Binding and catalysis are facilitated by hydrogen-bonding interactions in a hydrophobic pocket. The antagonists bind specifically to the same hydrogenbonding residues and induce a similar closed conformation. Thus, vitamin K antagonists act through mimicking the key interactions and conformational changes required for the VKOR catalytic cycle.
UR - http://www.scopus.com/inward/record.url?scp=85099154409&partnerID=8YFLogxK
U2 - 10.1126/science.abc5667
DO - 10.1126/science.abc5667
M3 - Article
C2 - 33154105
AN - SCOPUS:85099154409
SN - 0036-8075
VL - 371
JO - Science
JF - Science
IS - 6524
M1 - eabc5667
ER -