PDBsum entry 6ttt

Transferase

PDB id: 6ttt

Contents

Protein chains

198 a.a.

239 a.a.

Ligands

NWQ

ACT

Waters ×161

PDB id:

6ttt

Name:

Transferase

Title:

Crystal structure of the human mettl3-mettl14 complex bound to compound 2 (asi_m3m_140)

Structure:

N6-adenosine-methyltransferase catalytic subunit. Chain: a. Synonym: methyltransferase-like protein 3,hmettl3,n6-adenosine- methyltransferase 70 kda subunit,mt-a70. Engineered: yes. N6-adenosine-methyltransferase non-catalytic subunit. Chain: b. Synonym: methyltransferase-like protein 14,hmettl14. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: mettl3, mta70. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108. Gene: mettl14, kiaa1627. Expression_system_taxid: 7108

Resolution:

2.30Å R-factor: 0.193 R-free: 0.239

Authors:

R.K.Bedi,D.Huang,P.Sledz,A.Caflisch

Key ref:

R.K.Bedi et al. (2020). Small-Molecule Inhibitors of METTL3, the Major Human Epitranscriptomic Writer. ChemMedChem, 15, 744-748. PubMed id: 32159918 DOI: 10.1002/cmdc.202000011

Date:

30-Dec-19 Release date: 04-Mar-20

Protein chain

Q86U44  (MTA70_HUMAN) -  N6-adenosine-methyltransferase catalytic subunit from Homo sapiens

Seq: 580 a.a.

Struc: 198 a.a.

Protein chain

Q9HCE5  (MET14_HUMAN) -  N6-adenosine-methyltransferase non-catalytic subunit from Homo sapiens

Seq: 456 a.a.

Struc: 239 a.a.

Enzyme reactions

• Enzyme class: Chain A: E.C.2.1.1.348 - mRNA m(6)A methyltransferase.
• Reaction: an adenosine in mRNA + S-adenosyl-L-methionine = an N₆-methyladenosine in mRNA + S-adenosyl-L-homocysteine + H⁺

adenosine in mRNA + S-adenosyl-L-methionine = N(6)-methyladenosine in mRNA + S-adenosyl-L-homocysteine + H(+) (Bound ligand (Het Group name = NWQ) matches with 62.07% similarity)

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

Added reference

DOI no: 10.1002/cmdc.202000011

ChemMedChem 15:744-748 (2020)

PubMed id: 32159918

Small-Molecule Inhibitors of METTL3, the Major Human Epitranscriptomic Writer.

R.K.Bedi, D.Huang, S.A.Eberle, L.Wiedmer, P.Śledź, A.Caflisch.

ABSTRACT

The RNA methylase METTL3 catalyzes the transfer of a methyl group from the cofactor S-adenosyl-L-methionine (SAM) to the N⁶ atom of adenine. We have screened a library of 4000 analogues and derivatives of the adenosine moiety of SAM by high-throughput docking into METTL3. Two series of adenine derivatives were identified in silico, and the binding mode of six of the predicted inhibitors was validated by protein crystallography. Two compounds, one for each series, show good ligand efficiency. We propose a route for their further development into potent and selective inhibitors of METTL3.