7K6C

Crystal Structure of Dihydrofolate reductase (DHFR) from Mycobacterium abscessus ATCC 19977 / DSM 44196 with NADP and inhibitor P218

Summary for 7K6C

• Entry DOI: 10.2210/pdb7k6c/pdb
• Descriptor: Dihydrofolate reductase, NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE, 3-(2-{3-[(2,4-diamino-6-ethylpyrimidin-5-yl)oxy]propoxy}phenyl)propanoic acid, ... (6 entities in total)
• Functional Keywords: ssgcid, sddc, inhibitor, structural genomics, seattle structural genomics center for infectious disease, oxidoreductase, oxidoreductase-oxidoreductase inhibitor complex, oxidoreductase/oxidoreductase inhibitor
• Biological source: Mycobacteroides abscessus (strain ATCC 19977 / DSM 44196 / CIP 104536 / JCM 13569 / NCTC 13031 / TMC 1543)
• Total number of polymer chains: 7
• Total formula weight: 138810.07

Authors

Seattle Structural Genomics Center for Infectious Disease (SSGCID),Abendroth, J.,Santhakumar, V.,Walpole, C.,Lorimer, D.D.,Horanyi, P.S.,Edwards, T.E. (deposition date: 2020-09-19, release date: 2021-03-17, Last modification date: 2024-11-13)

Primary citation

Andrade Meirelles, M.,Almeida, V.M.,Sullivan, J.R.,de Toledo, I.,Dos Reis, C.V.,Cunha, M.R.,Zigweid, R.,Shim, A.,Sankaran, B.,Woodward, E.L.,Seibold, S.,Liu, L.,Mian, M.R.,Battaile, K.P.,Riley, J.,Duncan, C.,Simeons, F.R.C.,Ferguson, L.,Joji, H.,Read, K.D.,Lovell, S.,Staker, B.L.,Behr, M.A.,Pilli, R.A.,Counago, R.M.
Rational Exploration of 2,4-Diaminopyrimidines as DHFR Inhibitors Active against Mycobacterium abscessus and Mycobacterium avium , Two Emerging Human Pathogens.
J.Med.Chem., 2024

PubMed Abstract: Nontuberculous mycobacteria (NTM) are emerging human pathogens linked to severe pulmonary diseases. Current treatments involve the prolonged use of multiple drugs and are often ineffective. Bacterial dihydrofolate reductase (DHFR) is a key enzyme targeted by antibiotics in Gram-negative bacterial infections. However, existing DHFR inhibitors designed for Gram-negative bacteria often fail against mycobacterial DHFRs. Here, we detail the rational design of NTM DHFR inhibitors based on , a malarial DHFR inhibitor. We identified compound , a 2,4-diaminopyrimidine exhibiting improved pharmacological properties and activity against purified DHFR, and whole cell cultures of two predominant NTM species: and . This study underscores the potential of compound as a promising candidate for the validation of DHFR as an effective treatment against NTM infections.

PubMed: 39468773
DOI: 10.1021/acs.jmedchem.4c01594

Experimental method

X-RAY DIFFRACTION (2 Å)