Structure, function and inhibition of the two- and three-domain 4Fe-4S IspG proteins.

Proceedings of the National Academy of Sciences of the United States of America
Yi-Liang LiuEric Oldfield

Abstract

IspG is a 4Fe4S protein involved in isoprenoid biosynthesis. Most bacterial IspGs contain two domains: a TIM barrel (A) and a 4Fe4S domain (B), but in plants and malaria parasites, there is a large insert domain (A*) whose structure and function are unknown. We show that bacterial IspGs function in solution as (AB)(2) dimers and that mutations in either both A or both B domains block activity. Chimeras harboring an A-mutation in one chain and a B-mutation in the other have 50% of the activity seen in wild-type protein, because there is still one catalytically active AB domain. However, a plant IspG functions as an AA*B monomer. We propose, using computational modeling and electron microscopy, that the A* insert domain has a TIM barrel structure that interacts with the A domain. This structural arrangement enables the A and B domains to interact in a "cup and ball" manner during catalysis, just as in the bacterial systems. EPR/HYSCORE spectra of reaction intermediate, product, and inhibitor ligands bound to both two and three domain proteins are identical, indicating the same local electronic structure, and computational docking indicates these ligands bridge both A and B domains. Overall, the results are of broad general intere...Continue Reading

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Citations

Nov 2, 2013·Chemical Reviews·Alexander R MoiseEleanore T Wurtzel
Jun 13, 2012·Journal of the American Chemical Society·Weixue WangEric Oldfield
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May 13, 2014·Journal of the American Chemical Society·Ingrid SpanMichael Groll

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