PDBsum entry 6pvb

Transferase/transferase inhibitor

PDB id: 6pvb

Contents

Protein chain

225 a.a.

Ligands

P2J-GLZ-PRO-LYS-ARG-ILE-ALA-NH2

SAH

Waters ×163

PDB id:

6pvb

Name:

Transferase/transferase inhibitor

Title:

The structure of ntmt1 in complex with compound 6

Structure:

N-terminal xaa-pro-lys n-methyltransferase 1. Chain: b. Synonym: alpha n-terminal protein methyltransferase 1a, methyltransferase-like protein 11a,n-terminal rcc1 methyltransferase, x-pro-lys n-terminal protein methyltransferase 1a,ntm1a. Engineered: yes. Amino group-()-(2~{s})-2-azanylpropanal-()-isoleucine-()- arginine-()-lysine-()-proline-()-amino-acetaldehyde-()-9-(5-{[(3s)-3- amino-3-carboxypropyl](pentyl)amino}-5-deoxy-beta-l-

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: ntmt1, c9orf32, mettl11a, nrmt, nrmt1, ad-003. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008. Synthetic: yes. Synthetic construct. Organism_taxid: 32630

Resolution:

1.50Å R-factor: 0.206 R-free: 0.224

Authors:

N.Noinaj,D.Chen,R.Huang

Key ref:

D.Chen et al. (2020). Probing the Plasticity in the Active Site of Protein N-terminal Methyltransferase 1 Using Bisubstrate Analogues. J Med Chem, 63, 8419-8431. PubMed id: 32605369 DOI: 10.1021/acs.jmedchem.0c00770

Date:

20-Jul-19 Release date: 19-Aug-20

Protein chain

Q9BV86  (NTM1A_HUMAN) -  N-terminal Xaa-Pro-Lys N-methyltransferase 1 from Homo sapiens

Seq: 223 a.a.

Struc: 225 a.a.*

* PDB and UniProt seqs differ at 1 residue position (black cross)

Enzyme reactions

• Enzyme class: E.C.2.1.1.244 - protein N-terminal methyltransferase.
• Reaction:
  1. N-terminal L-alanyl-L-prolyl-L-lysyl-[protein] + 3 S-adenosyl-L- methionine = N-terminal N,N,N-trimethyl-L-alanyl-L-prolyl-L-lysyl- [protein] + 3 S-adenosyl-L-homocysteine + 3 H⁺
  2. N-terminal L-seryl-L-prolyl-L-lysyl-[protein] + 3 S-adenosyl-L- methionine = N-terminal N,N,N-trimethyl-L-seryl-L-prolyl-L-lysyl- [protein] + 3 S-adenosyl-L-homocysteine + 3 H⁺
  3. N-terminal L-prolyl-L-prolyl-L-lysyl-[protein] + 2 S-adenosyl-L- methionine = N-terminal N,N-dimethyl-L-prolyl-L-prolyl-L-lysyl-[protein] + 2 S-adenosyl-L-homocysteine + 2 H⁺

N-terminal L-alanyl-L-prolyl-L-lysyl-[protein] + 3 × S-adenosyl-L- methionine = N-terminal N,N,N-trimethyl-L-alanyl-L-prolyl-L-lysyl- [protein] + 3 × S-adenosyl-L-homocysteine + 3 × H(+) (Bound ligand (Het Group name = SAH) corresponds exactly)

N-terminal L-seryl-L-prolyl-L-lysyl-[protein] + 3 × S-adenosyl-L- methionine = N-terminal N,N,N-trimethyl-L-seryl-L-prolyl-L-lysyl- [protein] + 3 × S-adenosyl-L-homocysteine + 3 × H(+) (Bound ligand (Het Group name = SAH) corresponds exactly)

N-terminal L-prolyl-L-prolyl-L-lysyl-[protein] + 2 × S-adenosyl-L- methionine = N-terminal N,N-dimethyl-L-prolyl-L-prolyl-L-lysyl-[protein] + 2 × S-adenosyl-L-homocysteine + 2 × H(+) (Bound ligand (Het Group name = SAH) corresponds exactly)

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

reference

DOI no: 10.1021/acs.jmedchem.0c00770

J Med Chem 63:8419-8431 (2020)

PubMed id: 32605369

Probing the Plasticity in the Active Site of Protein N-terminal Methyltransferase 1 Using Bisubstrate Analogues.

D.Chen, C.Dong, G.Dong, K.Srinivasan, J.Min, N.Noinaj, R.Huang.

ABSTRACT

The bisubstrate analogue strategy is a promising approach to develop potent and selective inhibitors for protein methyltransferases. Herein, the interactions of a series of bisubstrate analogues with protein N-terminal methyltransferase 1 (NTMT1) were examined to probe the molecular properties of the active site of NTMT1. Our results indicate that a 2-C to 4-C atom linker enables its respective bisubstrate analogue to occupy both substrate- and cofactor-binding sites of NTMT1, but the bisubstrate analogue with a 5-C atom linker only interacts with the substrate-binding site and functions as a substrate. Furthermore, the 4-C atom linker is the optimal and produces the most potent inhibitor (K_i,app = 130 ± 40 pM) for NTMT1 to date, displaying more than 3000-fold selectivity for other methyltransferases and even for its homologue NTMT2. This study reveals the molecular basis for the plasticity of the active site of NTMT1. Additionally, our study outlines general guidance on the development of bisubstrate inhibitors for any methyltransferases.