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
June 14, 2025 at 7:35 PM
My favorite is the 'world tour' tee shirt 🤣🤣
Looking forward to this GRC!
Looking forward to this GRC!
June 4, 2025 at 1:24 AM
My favorite is the 'world tour' tee shirt 🤣🤣
Looking forward to this GRC!
Looking forward to this GRC!
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
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
Me, leaving the US for a conference in Europe.
March 15, 2025 at 12:25 AM
Me, leaving the US for a conference in Europe.
Yes! We do this for all the PhD students who graduate from our lab. Let me know if you want the name of my sword guy! 🗡️🧙♂️
March 11, 2025 at 12:15 AM
Yes! We do this for all the PhD students who graduate from our lab. Let me know if you want the name of my sword guy! 🗡️🧙♂️
Francis Collins brings down the house! 🎸🎸🎸
March 7, 2025 at 9:10 PM
Francis Collins brings down the house! 🎸🎸🎸
Great crowd and a great time at #StandUpForScience DC today at the Lincoln Memorial! @standupforscience.bsky.social
Photos… 🧵
Photos… 🧵
March 7, 2025 at 8:59 PM
Great crowd and a great time at #StandUpForScience DC today at the Lincoln Memorial! @standupforscience.bsky.social
Photos… 🧵
Photos… 🧵
Ready to #StandUpForScience tomorrow in DC! Let’s go! @standupforscience.bsky.social
March 6, 2025 at 12:52 PM
Ready to #StandUpForScience tomorrow in DC! Let’s go! @standupforscience.bsky.social
Final thoughts:
💡TRMT1 cleavage & inactivation may be another mechanism by which SARS-CoV-2 manipulates host tRNA modifications and translation!
🦠We think this could impact viral pathogenesis or phenotypes!
💊Our structure might help understand Mpro substrate recognition or different pockets to drug!
💡TRMT1 cleavage & inactivation may be another mechanism by which SARS-CoV-2 manipulates host tRNA modifications and translation!
🦠We think this could impact viral pathogenesis or phenotypes!
💊Our structure might help understand Mpro substrate recognition or different pockets to drug!
January 9, 2025 at 2:36 PM
Final thoughts:
💡TRMT1 cleavage & inactivation may be another mechanism by which SARS-CoV-2 manipulates host tRNA modifications and translation!
🦠We think this could impact viral pathogenesis or phenotypes!
💊Our structure might help understand Mpro substrate recognition or different pockets to drug!
💡TRMT1 cleavage & inactivation may be another mechanism by which SARS-CoV-2 manipulates host tRNA modifications and translation!
🦠We think this could impact viral pathogenesis or phenotypes!
💊Our structure might help understand Mpro substrate recognition or different pockets to drug!
Next, with @lucievirevolte.bsky.social we found that the TRMT1 cleavage sequence is highly conserved in mammals, except for some #rodents 🐭, where a Q -> K mutation at the absolutely critical Q residue makes TRMT1 variants with this change entirely resistant to cleavage!... 6/9
January 9, 2025 at 2:36 PM
Next, with @lucievirevolte.bsky.social we found that the TRMT1 cleavage sequence is highly conserved in mammals, except for some #rodents 🐭, where a Q -> K mutation at the absolutely critical Q residue makes TRMT1 variants with this change entirely resistant to cleavage!... 6/9
Angel also determined a beautiful structure of the TRMT1 cleavage sequence in complex with SARS-CoV-2 Mpro. The structure shows how the TRMT1 sequence binds to Mpro in a unique conformation, compared to most other viral polypeptide cleavage sequences (interesting for drug design?)... 5/9
January 9, 2025 at 2:36 PM
Angel also determined a beautiful structure of the TRMT1 cleavage sequence in complex with SARS-CoV-2 Mpro. The structure shows how the TRMT1 sequence binds to Mpro in a unique conformation, compared to most other viral polypeptide cleavage sequences (interesting for drug design?)... 5/9
Cleavage by the viral protease removes TRMT1's Zn finger 🖕 domain, weakening tRNA binding, but also *completely* inactivating TRMT1 methyltransferase activity!
The tRNA mods installed by TRMT1 are important for translation and redox homeostasis, so this could have impacts during infection!... 4/9
The tRNA mods installed by TRMT1 are important for translation and redox homeostasis, so this could have impacts during infection!... 4/9
January 9, 2025 at 2:36 PM
Cleavage by the viral protease removes TRMT1's Zn finger 🖕 domain, weakening tRNA binding, but also *completely* inactivating TRMT1 methyltransferase activity!
The tRNA mods installed by TRMT1 are important for translation and redox homeostasis, so this could have impacts during infection!... 4/9
The tRNA mods installed by TRMT1 are important for translation and redox homeostasis, so this could have impacts during infection!... 4/9
Angel D'Oliviera, a rockstar 🎸🌟 grad student in our lab, was able to show that not only do these proteins interact, but that SARS-CoV-2 Mpro can efficiently cleave endogenous, full-length TRMT1 in human cell lysate... 3/9
January 9, 2025 at 2:36 PM
Angel D'Oliviera, a rockstar 🎸🌟 grad student in our lab, was able to show that not only do these proteins interact, but that SARS-CoV-2 Mpro can efficiently cleave endogenous, full-length TRMT1 in human cell lysate... 3/9
January 1, 2025 at 10:29 PM