PDBsum entry 4xrb

Oxidoreductase

PDB id: 4xrb

Contents

Protein chain

246 a.a.

Ligands

NDP

PEG

Waters ×68

PDB id:

4xrb

Name:

Oxidoreductase

Title:

Crystal structure of rv2671 from mycobacterium tuberculosis

Structure:

Rv2671. Chain: a. Engineered: yes

Source:

Mycobacterium tuberculosis. Organism_taxid: 83332. Strain: atcc 25618 / h37rv. Gene: ribd, rv2671, rvbd_2671, lh57_14640, p425_02787. Expressed in: escherichia coli. Expression_system_taxid: 562

Resolution:

1.90Å R-factor: 0.177 R-free: 0.201

Authors:

Y.S.Cheng,J.C.Sacchettini,Tb Structural Genomics Consortium (Tbsgc)

Key ref:

Y.S.Cheng and J.C.Sacchettini (2016). Structural Insights into Mycobacterium tuberculosis Rv2671 Protein as a Dihydrofolate Reductase Functional Analogue Contributing to para-Aminosalicylic Acid Resistance. Biochemistry, 55, 1107-1119. PubMed id: 26848874 DOI: 10.1021/acs.biochem.5b00993

Date:

20-Jan-15 Release date: 24-Feb-16

Protein chain

P71968  (P71968_MYCTU) -  Bacterial bifunctional deaminase-reductase C-terminal domain-containing protein from Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv)

Seq: 258 a.a.

Struc: 246 a.a.

DOI no: 10.1021/acs.biochem.5b00993

Biochemistry 55:1107-1119 (2016)

PubMed id: 26848874

Structural Insights into Mycobacterium tuberculosis Rv2671 Protein as a Dihydrofolate Reductase Functional Analogue Contributing to para-Aminosalicylic Acid Resistance.

Y.S.Cheng, J.C.Sacchettini.

ABSTRACT

Mycobacterium tuberculosis (Mtb) Rv2671 is annotated as a 5-amino-6-ribitylamino-2,4(1H,3H)-pyrimidinedione 5'-phosphate (AROPP) reductase (RibD) in the riboflavin biosynthetic pathway. Recently, a strain of Mtb with a mutation in the 5' untranslated region of Rv2671, which resulted in its overexpression, was found to be resistant to dihydrofolate reductase (DHFR) inhibitors including the anti-Mtb drug para-aminosalicylic acid (PAS). In this study, a biochemical analysis of Rv2671 showed that it was able to catalyze the reduction of dihydrofolate (DHF) to tetrahydrofolate (THF), which explained why the overexpression of Rv2671 was sufficient to confer PAS resistance. We solved the structure of Rv2671 in complex with the NADP(+) and tetrahydrofolate (THF), which revealed the structural basis for the DHFR activity. The structures of Rv2671 complexed with two DHFR inhibitors, trimethoprim and trimetrexate, provided additional details of the substrate binding pocket and elucidated the differences between their inhibitory activities. Finally, Rv2671 was unable to catalyze the reduction of AROPP, which indicated that Rv2671 and its closely related orthologues are not involved in riboflavin biosynthesis.