PDBsum entry 6vsf

Biosynthetic protein

PDB id: 6vsf

Contents

Protein chains

159 a.a.

Ligands

RKY ×3

NAP ×2

GOL ×2

PO4 ×3

Metals

_CO ×2

Waters ×293

PDB id:

6vsf

Name:

Biosynthetic protein

Title:

Mycobacterium tuberculosis dihydrofolate reductase in complex with 4- (3,4-dihydro-2h-benzo[b][1,4]dioxepin-7-yl)-4-oxobutanoic acid(fragment 16)

Structure:

Dihydrofolate reductase. Chain: a, b. Engineered: yes

Source:

Mycobacterium tuberculosis (strain atcc 25618 / h37rv). Organism_taxid: 83332. Strain: atcc 25618 / h37rv. Gene: fola, dfra, rv2763c, mtv002.28c. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008.

Resolution:

2.01Å R-factor: 0.165 R-free: 0.211

Authors:

J.A.Ribeiro,M.V.B.Dias

Key ref:

J.A.Ribeiro et al. (2020). Using a Fragment-Based Approach to Identify Alternative Chemical Scaffolds Targeting Dihydrofolate Reductase from Mycobacterium tuberculosis. ACS Infect Dis, 6, 2192-2201. PubMed id: 32603583 DOI: 10.1021/acsinfecdis.0c00263

Date:

11-Feb-20 Release date: 15-Jul-20

Protein chains

P9WNX1  (DYR_MYCTU) -  Dihydrofolate reductase from Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv)

Seq: 161 a.a.

Struc: 159 a.a.

Enzyme reactions

• Enzyme class: E.C.1.5.1.3 - dihydrofolate reductase.
• Pathway: Folate Coenzymes
• Reaction: (6S)-5,6,7,8-tetrahydrofolate + NADP⁺ = 7,8-dihydrofolate + NADPH + H⁺

(6S)-5,6,7,8-tetrahydrofolate + NADP(+) (Bound ligand (Het Group name = NAP) corresponds exactly) = 7,8-dihydrofolate + NADPH + H(+)

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

reference

DOI no: 10.1021/acsinfecdis.0c00263

ACS Infect Dis 6:2192-2201 (2020)

PubMed id: 32603583

Using a Fragment-Based Approach to Identify Alternative Chemical Scaffolds Targeting Dihydrofolate Reductase from Mycobacterium tuberculosis.

J.A.Ribeiro, A.Hammer, G.A.Libreros-Zúñiga, S.M.Chavez-Pacheco, P.Tyrakis, G.S.de Oliveira, T.Kirkman, J.El Bakali, S.A.Rocco, M.L.Sforça, R.Parise-Filho, A.G.Coyne, T.L.Blundell, C.Abell, M.V.B.Dias.

ABSTRACT

Dihydrofolate reductase (DHFR), a key enzyme involved in folate metabolism, is a widely explored target in the treatment of cancer, immune diseases, bacteria, and protozoa infections. Although several antifolates have proved successful in the treatment of infectious diseases, they have been underexplored to combat tuberculosis, despite the essentiality of M. tuberculosis DHFR (MtDHFR). Herein, we describe an integrated fragment-based drug discovery approach to target MtDHFR that has identified hits with scaffolds not yet explored in any previous drug design campaign for this enzyme. The application of a SAR by catalog strategy of an in house library for one of the identified fragments has led to a series of molecules that bind to MtDHFR with low micromolar affinities. Crystal structures of MtDHFR in complex with compounds of this series demonstrated a novel binding mode that considerably differs from other DHFR antifolates, thus opening perspectives for the development of relevant MtDHFR inhibitors.