Crina Nimigean, Ph.D.

Research Summary:

Ion channels are key players in many physiological processes and their function is tightly regulated. The work in the lab is targeted towards understanding how ion channel structure and mechanism interrelate at the molecular level to fulfill diverse physiological needs. In particular, we are interested in ligand-gated ion channels and their allosteric regulation and we investigate them via a combination of structural, biochemical, biophysical, and electrophysiological approaches.  We use cryo-EM to determine high-resolution structures of ion channels in different conformations and in different lipid environments that we can directly assign to functional states via information from single-channel recording and other functional assays. This will ultimately pave the way towards conformationally-selective drug therapies.

Recent Publications:

1. Thon, O, Wang, Z, Schmidpeter, PAM, Nimigean, CM. PIP2 inhibits pore opening of the cyclic nucleotide-gated channel SthK. Nat Commun. 2024;15 (1):8230. doi: 10.1038/s41467-024-52469-1. PubMed PMID:39300080 PubMed Central PMC11413322.
2. Kim, ED, Wu, X, Lee, S, Tibbs, GR, Cunningham, KP, Di Zanni, E et al.. Propofol rescues voltage-dependent gating of HCN1 channel epilepsy mutants. Nature. 2024;632 (8024):451-459. doi: 10.1038/s41586-024-07743-z. PubMed PMID:39085604 .
3. Fan, C, Flood, E, Sukomon, N, Agarwal, S, Allen, TW, Nimigean, CM et al.. Calcium-gated potassium channel blockade via membrane-facing fenestrations. Nat Chem Biol. 2024;20 (1):52-61. doi: 10.1038/s41589-023-01406-2. PubMed PMID:37653172 PubMed Central PMC10847966.
4. Lansky, S, Betancourt, JM, Zhang, J, Jiang, Y, Kim, ED, Paknejad, N et al.. A pentameric TRPV3 channel with a dilated pore. Nature. 2023;621 (7977):206-214. doi: 10.1038/s41586-023-06470-1. PubMed PMID:37648856 PubMed Central PMC10584365.
5. Pan, Y, Pohjolainen, E, Schmidpeter, PAM, Vaiana, AC, Nimigean, CM, Grubmüller, H et al.. Discrimination between cyclic nucleotides in a cyclic nucleotide-gated ion channel. Nat Struct Mol Biol. 2023;30 (4):512-520. doi: 10.1038/s41594-023-00955-3. PubMed PMID:36973509 PubMed Central PMC10194703.
6. Schmidpeter, PAM, Petroff, JT 2nd, Khajoueinejad, L, Wague, A, Frankfater, C, Cheng, WWL et al.. Membrane phospholipids control gating of the mechanosensitive potassium leak channel TREK1. Nat Commun. 2023;14 (1):1077. doi: 10.1038/s41467-023-36765-w. PubMed PMID:36841877 PubMed Central PMC9968290.
7. Sukomon, N, Fan, C, Nimigean, CM. Ball-and-Chain Inactivation in Potassium Channels. Annu Rev Biophys. 2023;52 :91-111. doi: 10.1146/annurev-biophys-100322-072921. PubMed PMID:36626766 .
8. Gao, X, Schmidpeter, PAM, Berka, V, Durham, RJ, Fan, C, Jayaraman, V et al.. Gating intermediates reveal inhibitory role of the voltage sensor in a cyclic nucleotide-modulated ion channel. Nat Commun. 2022;13 (1):6919. doi: 10.1038/s41467-022-34673-z. PubMed PMID:36376326 PubMed Central PMC9663499.
9. Schmidpeter, PAM, Wu, D, Rheinberger, J, Riegelhaupt, PM, Tang, H, Robinson, CV et al.. Anionic lipids unlock the gates of select ion channels in the pacemaker family. Nat Struct Mol Biol. 2022;29 (11):1092-1100. doi: 10.1038/s41594-022-00851-2. PubMed PMID:36352139 PubMed Central PMC10022520.
10. Nimigean, CM. 35 years of channelling potassium ions. Nature. 2022;608 (7924):670-672. doi: 10.1038/d41586-022-02163-3. PubMed PMID:35970879 .
11. Sanganna Gari, RR, Montalvo-Acosta, JJ, Heath, GR, Jiang, Y, Gao, X, Nimigean, CM et al.. Correlation of membrane protein conformational and functional dynamics. Nat Commun. 2021;12 (1):4363. doi: 10.1038/s41467-021-24660-1. PubMed PMID:34272395 PubMed Central PMC8285522.
12. Schmidpeter, PAM, Nimigean, CM. Correlating ion channel structure and function. Methods Enzymol. 2021;652 :3-30. doi: 10.1016/bs.mie.2021.02.016. PubMed PMID:34059287 PubMed Central PMC9288845.
13. Wague, A, Joseph, TT, Woll, KA, Bu, W, Vaidya, KA, Bhanu, NV et al.. Mechanistic insights into volatile anesthetic modulation of K2P channels. Elife. 2020;9 :. doi: 10.7554/eLife.59839. PubMed PMID:33345771 PubMed Central PMC7781597.
14. Schmidpeter, PAM, Rheinberger, J, Nimigean, CM. Prolyl isomerization controls activation kinetics of a cyclic nucleotide-gated ion channel. Nat Commun. 2020;11 (1):6401. doi: 10.1038/s41467-020-20104-4. PubMed PMID:33328472 PubMed Central PMC7744796.
15. Tada, T, Fan, C, Chen, JS, Kaur, R, Stapleford, KA, Gristick, H et al.. An ACE2 Microbody Containing a Single Immunoglobulin Fc Domain Is a Potent Inhibitor of SARS-CoV-2. Cell Rep. 2020;33 (12):108528. doi: 10.1016/j.celrep.2020.108528. PubMed PMID:33326798 PubMed Central PMC7705358.
16. Boiteux, C, Posson, DJ, Allen, TW, Nimigean, CM. Selectivity filter ion binding affinity determines inactivation in a potassium channel. Proc Natl Acad Sci U S A. 2020;117 (47):29968-29978. doi: 10.1073/pnas.2009624117. PubMed PMID:33154158 PubMed Central PMC7703589.
17. Dandey, VP, Budell, WC, Wei, H, Bobe, D, Maruthi, K, Kopylov, M et al.. Time-resolved cryo-EM using Spotiton. Nat Methods. 2020;17 (9):897-900. doi: 10.1038/s41592-020-0925-6. PubMed PMID:32778833 PubMed Central PMC7799389.
18. Nimigean, CM. Polyamine block of MthK potassium channels. J Gen Physiol. 2020;152 (7):. doi: 10.1085/jgp.202012614. PubMed PMID:32459330 PubMed Central PMC7335008.
19. Fan, C, Sukomon, N, Flood, E, Rheinberger, J, Allen, TW, Nimigean, CM et al.. Ball-and-chain inactivation in a calcium-gated potassium channel. Nature. 2020;580 (7802):288-293. doi: 10.1038/s41586-020-2116-0. PubMed PMID:32269335 PubMed Central PMC7153497.
20. Schmidpeter, PAM, Sukomon, N, Nimigean, CM. Reconstitution of Membrane Proteins into Platforms Suitable for Biophysical and Structural Analyses. Methods Mol Biol. 2020;2127 :191-205. doi: 10.1007/978-1-0716-0373-4_14. PubMed PMID:32112324 PubMed Central PMC9288841.