8TA0
Crystal Structure of Dihydrofolate reductase (DHFR) from Mycobacterium ulcerans Agy99 in complex with NADP and inhibitor MAM881
Summary for 8TA0
| Entry DOI | 10.2210/pdb8ta0/pdb |
| Descriptor | Dihydrofolate reductase, 3-[2-(3-{[(6M)-2,4-diamino-6-(3-methoxyphenyl)pyrimidin-5-yl]oxy}propoxy)phenyl]propanoic acid, NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE, ... (4 entities in total) |
| Functional Keywords | ssgcid, structural genomics, seattle structural genomics center for infectious disease, dihydrofolate reductase, oxidoreductase-oxidoreductase inhibitor complex, oxidoreductase, oxidoreductase-inhibitor complex, oxidoreductase/inhibitor |
| Biological source | Mycobacterium ulcerans |
| Total number of polymer chains | 1 |
| Total formula weight | 20217.50 |
| Authors | Seattle Structural Genomics Center for Infectious Disease,Seattle Structural Genomics Center for Infectious Disease (SSGCID) (deposition date: 2023-06-26, release date: 2024-08-28, Last modification date: 2024-11-06) |
| 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 Cited by 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: 39468773DOI: 10.1021/acs.jmedchem.4c01594 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.95 Å) |
Structure validation
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