Structure of a bacterial homologue of vitamin K epoxide reductase

Weikai Li (), Sol Schulman, Rachel J. Dutton, Dana Boyd, Jon Beckwith and Tom A. Rapoport ()
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Weikai Li: Harvard Medical School, 240 Longwood Avenue, Boston, Massachusetts 02115, USA
Sol Schulman: Harvard Medical School, 240 Longwood Avenue, Boston, Massachusetts 02115, USA
Rachel J. Dutton: Harvard Medical School, 200 Longwood Avenue, Boston, Massachusetts 02115, USA
Dana Boyd: Harvard Medical School, 200 Longwood Avenue, Boston, Massachusetts 02115, USA
Jon Beckwith: Harvard Medical School, 200 Longwood Avenue, Boston, Massachusetts 02115, USA
Tom A. Rapoport: Harvard Medical School, 240 Longwood Avenue, Boston, Massachusetts 02115, USA

Nature, 2010, vol. 463, issue 7280, 507-512

Abstract: Abstract Vitamin K epoxide reductase (VKOR) generates vitamin K hydroquinone to sustain γ-carboxylation of many blood coagulation factors. Here, we report the 3.6 Å crystal structure of a bacterial homologue of VKOR from Synechococcus sp. The structure shows VKOR in complex with its naturally fused redox partner, a thioredoxin-like domain, and corresponds to an arrested state of electron transfer. The catalytic core of VKOR is a four transmembrane helix bundle that surrounds a quinone, connected through an additional transmembrane segment with the periplasmic thioredoxin-like domain. We propose a pathway for how VKOR uses electrons from cysteines of newly synthesized proteins to reduce a quinone, a mechanism confirmed by in vitro reconstitution of vitamin K-dependent disulphide bridge formation. Our results have implications for the mechanism of the mammalian VKOR and explain how mutations can cause resistance to the VKOR inhibitor warfarin, the most commonly used oral anticoagulant.

Date: 2010
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DOI: 10.1038/nature08720

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