PDBsum entry 6jvq

Hydrolase

PDB id: 6jvq

Contents

Protein chains

154 a.a.

Ligands

CJF ×2

Waters ×147

PDB id:

6jvq

Name:

Hydrolase

Title:

Crystal structure of human mth1 in complex with compound mi1025

Structure:

7,8-dihydro-8-oxoguanine triphosphatase. Chain: a, b. Synonym: 2-hydroxy-datp diphosphatase,8-oxo-dgtpase,nucleoside diphosphate-linked moiety x motif 1,nudix motif 1. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: nudt1, mth1. Expressed in: escherichia coli. Expression_system_taxid: 562.

Resolution:

2.20Å R-factor: 0.203 R-free: 0.266

Authors:

C.Peng,Y.H.Li,Y.S.Cheng

Key ref:

C.Peng et al. (2021). Inhibitor development of MTH1 via high-throughput screening with fragment based library and MTH1 substrate binding cavity. Bioorg Chem, 110, 104813. PubMed id: 33774493 DOI: 10.1016/j.bioorg.2021.104813

Date:

17-Apr-19 Release date: 28-Oct-20

Protein chains

P36639  (8ODP_HUMAN) -  Oxidized purine nucleoside triphosphate hydrolase from Homo sapiens

Seq: 156 a.a.

Struc: 154 a.a.

Enzyme reactions

• Enzyme class 2: E.C.3.6.1.- - ?????
• Enzyme class 3: E.C.3.6.1.56 - 2-hydroxy-dATP diphosphatase.
• Reaction: 2-oxo-dATP + H2O = 2-oxo-dAMP + diphosphate + H⁺

Note, where more than one E.C. class is given (as above), each may correspond to a different protein domain or, in the case of polyprotein precursors, to a different mature protein.

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

Key reference

DOI no: 10.1016/j.bioorg.2021.104813

Bioorg Chem 110:104813 (2021)

PubMed id: 33774493

Inhibitor development of MTH1 via high-throughput screening with fragment based library and MTH1 substrate binding cavity.

C.Peng, Y.H.Li, C.W.Yu, Z.H.Cheng, J.R.Liu, J.L.Hsu, L.W.Hsin, C.T.Huang, H.F.Juan, J.W.Chern, Y.S.Cheng.

ABSTRACT

MutT Homolog 1 (MTH1) has been proven to hydrolyze oxidized nucleotide triphosphates during DNA repair. It can prevent the incorporation of wrong nucleotides during DNA replication and mitigate cell apoptosis. In a cancer cell, abundant reactive oxygen species can lead to substantial DNA damage and DNA mutations by base-pairing mismatch. MTH1 could eliminate oxidized dNTP and prevent cancer cells from entering cell death. Therefore, inhibition of MTH1 activity is considered to be an anti-cancer therapeutic target. In this study, high-throughput screening techniques were combined with a fragment-based library containing 2,313 compounds, which were used to screen for lead compounds with MTH1 inhibitor activity. Four compounds with MTH1 inhibitor ability were selected, and compound MI0639 was found to have the highest effective inhibition. To discover the selectivity and specificity of this action, several derivatives based on the MTH1 and MI0639 complex structure were synthesized. We compared 14 complex structures of MTH1 and the various compounds in combination with enzymatic inhibition and thermodynamic analysis. Nanomolar-range IC₅₀ inhibition abilities by enzyme kinetics and K_d values by thermodynamic analysis were obtained for two compounds, named MI1020 and MI1024. Based on structural information and compound optimization, we aim to provide a strategy for the development of MTH1 inhibitors with high selectivity and specificity.