1KMV

HUMAN DIHYDROFOLATE REDUCTASE COMPLEXED WITH NADPH AND (Z)-6-(2-[2,5-DIMETHOXYPHENYL]ETHEN-1-YL)-2,4-DIAMINO-5-METHYLPYRIDO[2,3-D]PYRIMIDINE (SRI-9662), A LIPOPHILIC ANTIFOLATE

Summary for 1KMV

• Entry DOI: 10.2210/pdb1kmv/pdb
• Related: 1KMS
• Descriptor: DIHYDROFOLATE REDUCTASE, SULFATE ION, (Z)-6-(2-[2,5-DIMETHOXYPHENYL]ETHEN-1-YL)-2,4-DIAMINO-5-METHYLPYRIDO[2,3-D]PYRIMIDINE, ... (6 entities in total)
• Functional Keywords: oxidoreductase, antiparasitic drugs, reductase, lipophilic antifolates
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 22606.52

Authors

Klon, A.E.,Heroux, A.,Ross, L.J.,Pathak, V.,Johnson, C.A.,Piper, J.R.,Borhani, D.W. (deposition date: 2001-12-17, release date: 2002-07-10, Last modification date: 2024-04-03)

Primary citation

Klon, A.E.,Heroux, A.,Ross, L.J.,Pathak, V.,Johnson, C.A.,Piper, J.R.,Borhani, D.W.
Atomic structures of human dihydrofolate reductase complexed with NADPH and two lipophilic antifolates at 1.09 a and 1.05 a resolution.
J.Mol.Biol., 320:677-693, 2002

PubMed Abstract: The crystal structures of two human dihydrofolate reductase (hDHFR) ternary complexes, each with bound NADPH cofactor and a lipophilic antifolate inhibitor, have been determined at atomic resolution. The potent inhibitors 6-([5-quinolylamino]methyl)-2,4-diamino-5-methylpyrido[2,3-d]pyrimidine (SRI-9439) and (Z)-6-(2-[2,5-dimethoxyphenyl]ethen-1-yl)-2,4-diamino-5-methylpyrido[2,3-d]pyrimidine (SRI-9662) were developed at Southern Research Institute against Toxoplasma gondii DHFR-thymidylate synthase. The 5-deazapteridine ring of each inhibitor adopts an unusual puckered conformation that enables the formation of identical contacts in the active site. Conversely, the quinoline and dimethoxybenzene moieties exhibit distinct binding characteristics that account for the differences in inhibitory activity. In both structures, a salt-bridge is formed between Arg70 in the active site and Glu44 from a symmetry-related molecule in the crystal lattice that mimics the binding of methotrexate to DHFR.

PubMed: 12096917
DOI: 10.1016/S0022-2836(02)00469-2

Experimental method

X-RAY DIFFRACTION (1.05 Å)