2CD2

LIGAND INDUCED CONFORMATIONAL CHANGES IN THE CRYSTAL STRUCTURES OF PNEUMOCYSTIS CARINII DIHYDROFOLATE REDUCTASE COMPLEXES WITH FOLATE AND NADP+

2CD2 の概要

• エントリーDOI: 10.2210/pdb2cd2/pdb
• 関連するPDBエントリー: 1CD2 3CD2 4CD2
• 分子名称: DIHYDROFOLATE REDUCTASE, NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE, FOLIC ACID, ... (4 entities in total)
• 機能のキーワード: oxido-reductase, folate, nadph, oxidoreductase
• 由来する生物種: Pneumocystis carinii
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 25103.34

構造登録者

Cody, V.,Galitsky, N.,Rak, D.,Luft, J.,Pangborn, W.,Queener, S. (登録日: 1999-03-15, 公開日: 2000-03-29, 最終更新日: 2023-12-27)

主引用文献

Cody, V.,Galitsky, N.,Rak, D.,Luft, J.R.,Pangborn, W.,Queener, S.F.
Ligand-induced conformational changes in the crystal structures of Pneumocystis carinii dihydrofolate reductase complexes with folate and NADP+.
Biochemistry, 38:4303-4312, 1999

PubMed Abstract: Structural data from two independent crystal forms (P212121 and P21) of the folate (FA) binary complex and from the ternary complex with the oxidized coenzyme, NADP+, and recombinant Pneumocystis carinii dihydrofolate reductase (pcDHFR) refined to an average of 2.15 A resolution, show the first evidence of ligand-induced conformational changes in the structure of pcDHFR. These data are also compared with the crystal structure of the ternary complex of methotrexate (MTX) with NADPH and pcDHFR in the monoclinic lattice with data to 2.5 A resolution. Comparison of the data for the FA binary complex of pcDHFR with those for the ternary structures reveals significant differences, with a >7 A movement of the loop region near residue 23 that results in a new "flap-open" position for the binary complex, and a "closed" position in the ternary complexes, similar to that reported for Escherichia coli (ec) DHFR complexes. In the orthorhombic lattice for the binary FA pcDHFR complex, there is also an unwinding of a short helical region near residue 47 that places hydrophobic residues Phe-46 and Phe-49 toward the outer surface, a conformation that is stabilized by intermolecular packing contacts. The pyrophosphate moiety of NADP+ in the ternary folate pcDHFR complexes shows significant differences in conformation compared with that observed in the MTX-NADPH-pcDHFR ternary complex. Additionally, comparison of the conformations among these four pcDHFR structures reveals evidence for subdomain movement that correlates with cofactor binding states. The larger binding site access in the new "flap-open" loop 23 conformation of the binary FA complex is consistent with the rapid release of cofactor from the product complex during catalysis as well as the more rapid release of substrate product from the binary complex as a result of the weaker contacts of the closed loop 23 conformation, compared to ecDHFR.

PubMed: 10194348
DOI: 10.1021/bi982728m

実験手法

X-RAY DIFFRACTION (1.9 Å)