Modomics - A Database of RNA Modifications

ID Card:

Full name: tRNA methyltransferase 1
UniProt: Q9NXH9
Structures: | 8D35 |
Alpha Fold Predicted Structure: AF-Q9NXH9-F1
Enzyme type: methyltransferase


PDB Structures:


8D35

Structure Description:

Title:
Classification:
Technique:

Abstract of the PDB Structure's related Publication:

The SARS-CoV-2 main protease (M pro ) plays a crucial role in the production of functional viral proteins during infection and, like many viral proteases, can also target and cleave host proteins to subvert their cellular functions. Here, we show that the human tRNA methyltransferase TRMT1 can be recognized and cleaved by SARS-CoV-2 M pro . TRMT1 installs the N2,N2-dimethylguanosine (m2,2G) modification at the G26 position of mammalian tRNA, which promotes global protein synthesis, cellular redox homeostasis, and has links to neurological disability. We find that M pro can cleave endogenous TRMT1 in human cell lysate, resulting in removal of the TRMT1 zinc finger domain that is required for tRNA modification activity in cells. Evolutionary analysis shows that the TRMT1 cleavage site is highly conserved in mammals, except in Muroidea, where TRMT1 may be resistant to cleavage. In primates, regions outside of the cleavage site with rapid evolution could indicate possible adaptation to ancient viral pathogens. To visualize how M pro recognizes the TRMT1 cleavage sequence, we determined the structure of a TRMT1 peptide in complex with M pro , which reveals a substrate binding conformation distinct from the majority of available SARS-CoV-2 M pro -peptide complexes. Kinetic parameters for peptide cleavage showed that while TRMT1(526-536) is cleaved much slower than the M pro nsp4/5 autoprocessing sequence, it is proteolyzed with comparable efficiency to the M pro -targeted nsp8/9 viral cleavage site. Mutagenesis studies and molecular dynamics simulations together indicate that kinetic discrimination occurs during a later step of M pro -mediated proteolysis that follows substrate binding. Our results provide new information about the structural basis for M pro substrate recognition and cleavage that could help inform future therapeutic design and raise the possibility that proteolysis of human TRMT1 during SARS-CoV-2 infection may impact protein translation or oxidative stress response and contribute to viral pathogenesis.

Download RCSB-PDB Structures:

Pdb Files   8D35.pdb  
Pdbx/mmCIF Files   8D35.cif  


Protein sequence:

MQGSSLWLSLTFRSARVLSRARFFEWQSPGLPNTAAMENGTGPYGEERPREVQETTVTEGAAKIAFPSANEVFYNPVQEFNRDLTCAVITEFARIQLGAKGIQIKVPGEKDTQKVVVDLSEQEEEKVELKESENLASGDQPRTAAVGEICEEGLHVLEGLAASGLRSIRFALEVPGLRSVVANDASTRAVDLIRRNVQLNDVAHLVQPSQADARMLMYQHQRVSERFDVIDLDPYGSPATFLDAAVQAVSEGGLLCVTCTDMAVLAGNSGETCYSKYGAMALKSRACHEMALRIVLHSLDLRANCYQRFVVPLLSISADFYVRVFVRVFTGQAKVKASASKQALVFQCVGCGAFHLQRLGKASGVPSGRAKFSAACGPPVTPECEHCGQRHQLGGPMWAEPIHDLDFVGRVLEAVSANPGRFHTSERIRGVLSVITEELPDVPLYYTLDQLSSTIHCNTPSLLQLRSALLHADFRVSLSHACKNAVKTDAPASALWDIMRCWEKECPVKRERLSETSPAFRILSVEPRLQANFTIREDANPSSRQRGLKRFQANPEANWGPRPRARPGGKAADEAMEERRRLLQNKRKEPPEDVAQRAARLKTFPCKRFKEGTCQRGDQCCYSHSPPTPRVSADAAPDCPETSNQTPPGPGAAAGPGID

Comments:

TRMT1 independently catalyzes formation of the tRNA:m2G26 or m22G26 modification in a substrate-dependent manner





Alpha Fold Predicted Structure:






Clear Selection and Reset Camera

Protein sequence:

M Q G S S L W L S L T F R S A R V L S R A R F F E W Q S P G L P N T A A M E N G T G P Y G E E R P R E V Q E T T V T E G A A K I A F P S A N E V F Y N P V Q E F N R D L T C A V I T E F A R I Q L G A K G I Q I K V P G E K D T Q K V V V D L S E Q E E E K V E L K E S E N L A S G D Q P R T A A V G E I C E E G L H V L E G L A A S G L R S I R F A L E V P G L R S V V A N D A S T R A V D L I R R N V Q L N D V A H L V Q P S Q A D A R M L M Y Q H Q R V S E R F D V I D L D P Y G S P A T F L D A A V Q A V S E G G L L C V T C T D M A V L A G N S G E T C Y S K Y G A M A L K S R A C H E M A L R I V L H S L D L R A N C Y Q R F V V P L L S I S A D F Y V R V F V R V F T G Q A K V K A S A S K Q A L V F Q C V G C G A F H L Q R L G K A S G V P S G R A K F S A A C G P P V T P E C E H C G Q R H Q L G G P M W A E P I H D L D F V G R V L E A V S A N P G R F H T S E R I R G V L S V I T E E L P D V P L Y Y T L D Q L S S T I H C N T P S L L Q L R S A L L H A D F R V S L S H A C K N A V K T D A P A S A L W D I M R C W E K E C P V K R E R L S E T S P A F R I L S V E P R L Q A N F T I R E D A N P S S R Q R G L K R F Q A N P E A N W G P R P R A R P G G K A A D E A M E E R R R L L Q N K R K E P P E D V A Q R A A R L K T F P C K R F K E G T C Q R G D Q C C Y S H S P P T P R V S A D A A P D C P E T S N Q T P P G P G A A A G P G I D

Secondary Structure Alphabet

  • G: 3-turn helix (310helix)
  • H: α-helix
  • I: 𝝅-helix (5 - turn helix)
  • T: Hydrogen Bonded Turn
  • B: β-sheet
  • S: Bend
  • C: Coil (residues not present in any of the above conformations)
  • N: Not assigned

Download PDB Structures & DSSP Secondary Structures:

Alpha Fold Pdb Files   AF-Q9NXH9-F1.pdb  
Alpha Fold Pdbx/mmCIF Files   AF-Q9NXH9-F1.cif  
DSSP Secondary Structures   Q9NXH9.dssp  





Publications:

Title Authors Journal Details PubMed Id DOI
TRMT1-Catalyzed tRNA Modifications Are Required for Redox Homeostasis To Ensure Proper Cellular Proliferation and Oxidative Stress Survival Joshua M Dewe 1, Benjamin L Fuller 1, Jenna M Lentini 1, Stefanie M Kellner 2, Dragony Fu [details] 28784718 10.1128/MCB.00214-17
Human TRMT1 catalyzes m2G or m22G formation on tRNAs in a substrate-dependent manner Qing-Ping Xiong 1, Jing Li 2, Hao Li 2, Zhi-Xuan Huang 1 2, Han Dong 1, En-Duo Wang 3 4, Ru-Juan Liu [details] 37204604 10.1007/s11427-022-2295-0