4XT4

Crystal structure of Rv2671 from Mycobacteirum tuberculosis in complex with dihydropteridine ring of dihydropteroic acid

Summary for 4XT4

• Entry DOI: 10.2210/pdb4xt4/pdb
• Related: 4XRB 4XT5 4XT6 4XT7 4XT8
• Descriptor: Rv2671, NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE, 2-amino-6-methyl-7,8-dihydropteridin-4(3H)-one, ... (5 entities in total)
• Functional Keywords: reductase, pteridine, structural genomics, tb structural genomics consortium, tbsgc, oxidoreductase
• Biological source: Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv)
• Total number of polymer chains: 1
• Total formula weight: 28828.27

Authors

Sacchettini, J.C.,Cheng, Y.S.,TB Structural Genomics Consortium (TBSGC) (deposition date: 2015-01-22, release date: 2016-02-24, Last modification date: 2023-09-27)

Primary citation

Cheng, Y.S.,Sacchettini, J.C.
Structural Insights into Mycobacterium tuberculosis Rv2671 Protein as a Dihydrofolate Reductase Functional Analogue Contributing to para-Aminosalicylic Acid Resistance.
Biochemistry, 55:1107-1119, 2016

PubMed 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.

PubMed: 26848874
DOI: 10.1021/acs.biochem.5b00993

Experimental method

X-RAY DIFFRACTION (1.891 Å)