Jeff Mugridge
@jeffmugridge.bsky.social
I'm a scientist! Asst Prof at Univ of Delaware | RNA biochemistry, RNA modifications, (metallo)enzymology, structural biology, and chemistry | Postdoc at UCSF | PhD at UCBerkeley | he/him
mugridgelab.org
mugridgelab.org
Thanks for hosting me! Really fun visit to UMBC and heard about lots of great science!
November 8, 2025 at 1:14 PM
Thanks for hosting me! Really fun visit to UMBC and heard about lots of great science!
Reposted by Jeff Mugridge
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June 10, 2025 at 4:10 AM
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As far as we know, this is only the ~2nd example of a molecular tunnel connecting active sites in radical SAM enzymes, and the 1st example of acetate transport in an enzyme!
We're working on more pieces of this puzzle to show how Elp3/Elongator tRNA modification is regulated!
Congrats Evan! 9/9
We're working on more pieces of this puzzle to show how Elp3/Elongator tRNA modification is regulated!
Congrats Evan! 9/9
May 8, 2025 at 2:46 PM
As far as we know, this is only the ~2nd example of a molecular tunnel connecting active sites in radical SAM enzymes, and the 1st example of acetate transport in an enzyme!
We're working on more pieces of this puzzle to show how Elp3/Elongator tRNA modification is regulated!
Congrats Evan! 9/9
We're working on more pieces of this puzzle to show how Elp3/Elongator tRNA modification is regulated!
Congrats Evan! 9/9
See lots more experiments in the paper, but we propose a new model for Elp3/Elongator tRNA modification where Elp3 hydrolyzes acteyl-CoA to release acetate into the molecular tunnel which transports it to the RS active site for radical chemistry and tRNA modification! 8/9
May 8, 2025 at 2:46 PM
See lots more experiments in the paper, but we propose a new model for Elp3/Elongator tRNA modification where Elp3 hydrolyzes acteyl-CoA to release acetate into the molecular tunnel which transports it to the RS active site for radical chemistry and tRNA modification! 8/9
Evan next showed that if you *block* the molecular tunnel by mutating a tunnel-lining residue to Trp, you cripple tRNA modification activity without affecting tRNA binding or acetyl-CoA binding and turnover much. 7/9
May 8, 2025 at 2:46 PM
Evan next showed that if you *block* the molecular tunnel by mutating a tunnel-lining residue to Trp, you cripple tRNA modification activity without affecting tRNA binding or acetyl-CoA binding and turnover much. 7/9
With active Elp3, now we can do some enzymology! To test our acetate hypothesis, Evan showed that if you do Elp3 tRNA modification reactions where you *leave out* acetyl-CoA, but give the enzyme acetate, it still works! 6/9
May 8, 2025 at 2:46 PM
With active Elp3, now we can do some enzymology! To test our acetate hypothesis, Evan showed that if you do Elp3 tRNA modification reactions where you *leave out* acetyl-CoA, but give the enzyme acetate, it still works! 6/9
Let's test that! ONE PROBLEM: Elp3 is notoriously difficult to work with because its [4Fe-4S] cluster is very air sensitive. BUT after lots of work in our glovebox, grad student Evan Geissler was able to reconstitute in vitro Elp3 tRNA modification activity for the first time in over a decade!! 5/9
a room with a sign that says exit and a gifbin.com logo in the corner
Alt: animated GIF showing a scientist giving high fives to the gloves on an air-free glovebox. Evan was happy too when he got Elp3 activity!
media.tenor.com
May 8, 2025 at 2:46 PM
Let's test that! ONE PROBLEM: Elp3 is notoriously difficult to work with because its [4Fe-4S] cluster is very air sensitive. BUT after lots of work in our glovebox, grad student Evan Geissler was able to reconstitute in vitro Elp3 tRNA modification activity for the first time in over a decade!! 5/9
When we looked closely at structures of recent Elongator-tRNA complexes, we found when tRNA binds Elp3 it creates an enclosed *molecular tunnel* that connects the acetyl-CoA binding site and radical SAM active site of Elp3! Could the enzyme use the tunnel to transport *acetate* to make cm5U? 4/9
May 8, 2025 at 2:46 PM
When we looked closely at structures of recent Elongator-tRNA complexes, we found when tRNA binds Elp3 it creates an enclosed *molecular tunnel* that connects the acetyl-CoA binding site and radical SAM active site of Elp3! Could the enzyme use the tunnel to transport *acetate* to make cm5U? 4/9
...in all the Elp3 and Elongator structures that have been determined, the acetyl-CoA binding site is over 20 A away from the radical SAM site where the modification chemistry happens! How does acetyl-CoA or its acetyl group get all the way across the enzyme? 3/9
May 8, 2025 at 2:46 PM
...in all the Elp3 and Elongator structures that have been determined, the acetyl-CoA binding site is over 20 A away from the radical SAM site where the modification chemistry happens! How does acetyl-CoA or its acetyl group get all the way across the enzyme? 3/9
Elp3, which in eukaryotes functions as part of the Elongator complex, installs the really important intermediate modification cm5U on the wobble base of tRNAs. The cm5U carbon and oxygen atoms (in red) come from cofactor acetyl-CoA. BUT... 2/9
May 8, 2025 at 2:46 PM
Elp3, which in eukaryotes functions as part of the Elongator complex, installs the really important intermediate modification cm5U on the wobble base of tRNAs. The cm5U carbon and oxygen atoms (in red) come from cofactor acetyl-CoA. BUT... 2/9