Breaking Cryo-EM Resolution Barriers to Facilitate Drug Discovery. Merk, A., Bartesaghi, A., Banerjee, S., Falconieri, V., Rao, P., Davis, M., I., Pragani, R., Boxer, M., B., Earl, L., A., Milne, J., L., & Subramaniam, S. Cell, 165(7):1698-1707, 6, 2016.
Breaking Cryo-EM Resolution Barriers to Facilitate Drug Discovery [link]Website  abstract   bibtex   
Recent advances in single-particle cryoelecton microscopy (cryo-EM) are enabling generation of numerous near-atomic resolution structures for well-ordered protein complexes with sizes ≥ ∼200 kDa. Whether cryo-EM methods are equally useful for high-resolution structural analysis of smaller, dynamic protein complexes such as those involved in cellular metabolism remains an important question. Here, we present 3.8 Å resolution cryo-EM structures of the cancer target isocitrate dehydrogenase (93 kDa) and identify the nature of conformational changes induced by binding of the allosteric small-molecule inhibitor ML309. We also report 2.8-Å- and 1.8-Å-resolution structures of lactate dehydrogenase (145 kDa) and glutamate dehydrogenase (334 kDa), respectively. With these results, two perceived barriers in single-particle cryo-EM are overcome: (1) crossing 2 Å resolution and (2) obtaining structures of proteins with sizes < 100 kDa, demonstrating that cryo-EM can be used to investigate a broad spectrum of drug-target interactions and dynamic conformational states.
@article{
 title = {Breaking Cryo-EM Resolution Barriers to Facilitate Drug Discovery},
 type = {article},
 year = {2016},
 identifiers = {[object Object]},
 pages = {1698-1707},
 volume = {165},
 websites = {http://www.ncbi.nlm.nih.gov/pubmed/27238019},
 month = {6},
 day = {16},
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 abstract = {Recent advances in single-particle cryoelecton microscopy (cryo-EM) are enabling generation of numerous near-atomic resolution structures for well-ordered protein complexes with sizes ≥ ∼200 kDa. Whether cryo-EM methods are equally useful for high-resolution structural analysis of smaller, dynamic protein complexes such as those involved in cellular metabolism remains an important question. Here, we present 3.8 Å resolution cryo-EM structures of the cancer target isocitrate dehydrogenase (93 kDa) and identify the nature of conformational changes induced by binding of the allosteric small-molecule inhibitor ML309. We also report 2.8-Å- and 1.8-Å-resolution structures of lactate dehydrogenase (145 kDa) and glutamate dehydrogenase (334 kDa), respectively. With these results, two perceived barriers in single-particle cryo-EM are overcome: (1) crossing 2 Å resolution and (2) obtaining structures of proteins with sizes < 100 kDa, demonstrating that cryo-EM can be used to investigate a broad spectrum of drug-target interactions and dynamic conformational states.},
 bibtype = {article},
 author = {Merk, Alan and Bartesaghi, Alberto and Banerjee, Soojay and Falconieri, Veronica and Rao, Prashant and Davis, Mindy I. and Pragani, Rajan and Boxer, Matthew B. and Earl, Lesley A. and Milne, Jacqueline L.S. and Subramaniam, Sriram},
 journal = {Cell},
 number = {7}
}
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