PDBsum entry 6fxh

Hydrolase

PDB id: 6fxh

Contents

Protein chain

481 a.a.

Ligands

SO4 ×5

GOL ×4

Metals

_MG ×2

Waters ×223

PDB id:

6fxh

Name:

Hydrolase

Title:

Human cytosolic 5'-nucleotidase ii soaked with 10mm 3-phenyl-n-(9h- purin-6-yl)benzamide

Structure:

Cytosolic purine 5'-nucleotidase. Chain: a. Synonym: cytosolic 5'-nucleotidase ii. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: nt5c2, nt5b, nt5cp, pnt5. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008. Expression_system_variant: rosetta2.

Resolution:

2.30Å R-factor: 0.180 R-free: 0.235

Authors:

N.Aghajari,P.Preeti

Key ref:

R.Guillon et al. (2019). Lead optimization and biological evaluation of fragment-based cN-II inhibitors. Eur J Med Chem, 168, 28-44. PubMed id: 30798051 DOI: 10.1016/j.ejmech.2019.02.040

Date:

09-Mar-18 Release date: 06-Mar-19

Protein chain

P49902  (5NTC_HUMAN) -  Cytosolic purine 5'-nucleotidase from Homo sapiens

Seq: 561 a.a.

Struc: 481 a.a.

Enzyme reactions

• Enzyme class 2: E.C.2.7.1.77 - nucleoside phosphotransferase.
• Reaction: a 2'-deoxyribonucleoside + a ribonucleoside 5'-phosphate = a ribonucleoside + a 2'-deoxyribonucleoside 5'-phosphate

2'-deoxyribonucleoside + ribonucleoside 5'-phosphate = ribonucleoside + 2'-deoxyribonucleoside 5'-phosphate (Bound ligand (Het Group name = GOL) matches with 60.00% similarity)

• Enzyme class 3: E.C.3.1.3.5 - 5'-nucleotidase.
• Reaction: a ribonucleoside 5'-phosphate + H2O = a ribonucleoside + phosphate

ribonucleoside 5'-phosphate + H2O = ribonucleoside (Bound ligand (Het Group name = GOL) matches with 60.00% similarity) + phosphate

• Enzyme class 4: E.C.3.1.3.99 - IMP-specific 5'-nucleotidase.
• Reaction: IMP + H2O = inosine + phosphate
• Cofactor: Divalent metal cation

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

reference

DOI no: 10.1016/j.ejmech.2019.02.040

Eur J Med Chem 168:28-44 (2019)

PubMed id: 30798051

Lead optimization and biological evaluation of fragment-based cN-II inhibitors.

R.Guillon, R.Rahimova, Preeti, D.Egron, S.Rouanet, C.Dumontet, N.Aghajari, L.P.Jordheim, L.Chaloin, S.Peyrottes.

ABSTRACT

The development of cytosolic 5'-nucleotidase II (cN-II) inhibitors is essential to validate cN-II as a potential target for the reversion of resistance to cytotoxic nucleoside analogues. We previously reported a fragment-based approach combined with molecular modelling, herein, the selected hit-fragments were used again in another computational approach based on the Ilib-diverse (a software enabling to build virtual molecule libraries through fragment based de novo design) program to generate a focused library of potential inhibitors. A molecular scaffold related to a previously identified compound was selected and led to a novel series of compounds. Ten out of nineteen derivatives showed 50-75% inhibition on the purified recombinant protein at 200 μM and among them three derivatives (12, 13 and 18) exhibited K_i in the sub-millimolar range (0.84, 2.4 and 0.58 mM, respectively). Despite their only modest potency, the cN-II inhibitors showed synergistic effects when used in combination with cytotoxic purine nucleoside analogues on cancer cells. Therefore, these derivatives represent a family of non-nucleos(t)idic cN-II inhibitors with potential usefulness to overcome cancer drug resistance especially in hematological malignancies in which cN-II activity has been described as an important parameter.