EMDB/PDB/SASBDBから引用されている文献のデータベース

キーワード
構造解析手法	All X線回折 NMR 電子顕微鏡小角散乱中性子線回折線維回折粉末回折赤外分光 EPR FRET 理論モデルハイブリッド
著者・登録者
ジャーナル
IF	>30 >20 >10 >5 all

タイトル	A hybrid approach reveals the allosteric regulation of GTP cyclohydrolase I.
ジャーナル・号・ページ	Proc Natl Acad Sci U S A, Vol. 117, Issue 50, Page 31838-31849, Year 2020
掲載日	2020年12月15日
著者	Rebecca Ebenhoch / Simone Prinz / Susann Kaltwasser / Deryck J Mills / Robert Meinecke / Martin Rübbelke / Dirk Reinert / Margit Bauer / Lisa Weixler / Markus Zeeb / Janet Vonck / Herbert Nar /
PubMed 要旨	Guanosine triphosphate (GTP) cyclohydrolase I (GCH1) catalyzes the conversion of GTP to dihydroneopterin triphosphate (H2NTP), the initiating step in the biosynthesis of tetrahydrobiopterin (BH4). ...Guanosine triphosphate (GTP) cyclohydrolase I (GCH1) catalyzes the conversion of GTP to dihydroneopterin triphosphate (H2NTP), the initiating step in the biosynthesis of tetrahydrobiopterin (BH4). Besides other roles, BH4 functions as cofactor in neurotransmitter biosynthesis. The BH4 biosynthetic pathway and GCH1 have been identified as promising targets to treat pain disorders in patients. The function of mammalian GCH1s is regulated by a metabolic sensing mechanism involving a regulator protein, GCH1 feedback regulatory protein (GFRP). GFRP binds to GCH1 to form inhibited or activated complexes dependent on availability of cofactor ligands, BH4 and phenylalanine, respectively. We determined high-resolution structures of human GCH1-GFRP complexes by cryoelectron microscopy (cryo-EM). Cryo-EM revealed structural flexibility of specific and relevant surface lining loops, which previously was not detected by X-ray crystallography due to crystal packing effects. Further, we studied allosteric regulation of isolated GCH1 by X-ray crystallography. Using the combined structural information, we are able to obtain a comprehensive picture of the mechanism of allosteric regulation. Local rearrangements in the allosteric pocket upon BH4 binding result in drastic changes in the quaternary structure of the enzyme, leading to a more compact, tense form of the inhibited protein, and translocate to the active site, leading to an open, more flexible structure of its surroundings. Inhibition of the enzymatic activity is not a result of hindrance of substrate binding, but rather a consequence of accelerated substrate binding kinetics as shown by saturation transfer difference NMR (STD-NMR) and site-directed mutagenesis. We propose a dissociation rate controlled mechanism of allosteric, noncompetitive inhibition.
リンク	Proc Natl Acad Sci U S A / PubMed:33229582 / PubMed Central
手法	EM (単粒子) / X線回折
解像度	1.726 - 3.0 Å
構造データ	11113 6z80 EMDB-11113, PDB-6z80: stimulatory human GTP cyclohydrolase I - GFRP complex 手法: EM (単粒子) / 解像度: 3.0 Å 11114 6z85 EMDB-11114, PDB-6z85: inhibitory human GTP cyclohydrolase I - GFRP complex 手法: EM (単粒子) / 解像度: 2.9 Å PDB-6z86: human GTP cyclohydrolase I in complex with 7-deaza-GTP 手法: X-RAY DIFFRACTION / 解像度: 2.206 Å PDB-6z87: human GTP cyclohydrolase I 手法: X-RAY DIFFRACTION / 解像度: 2.564 Å PDB-6z88: human GTP cyclohydrolase I in complex with allosteric inhibitor 手法: X-RAY DIFFRACTION / 解像度: 2.687 Å PDB-6z89: human GTP cyclohydrolase I in complex with allosteric inhibitor 手法: X-RAY DIFFRACTION / 解像度: 2.366 Å PDB-7acc: human GTP cyclohydrolase I feedback regulatory protein (GFRP) 手法: X-RAY DIFFRACTION / 解像度: 2.04 Å PDB-7al9: human GTP cyclohydrolase I feedback regulatory protein (GFRP) in complex with phenylalanine 手法: X-RAY DIFFRACTION / 解像度: 1.745 Å PDB-7ala: human GCH-GFRP inhibitory complex 手法: X-RAY DIFFRACTION / 解像度: 1.846 Å PDB-7alb: human GCH-GFRP stimulatory complex 7-deaza-GTP bound 手法: X-RAY DIFFRACTION / 解像度: 1.979 Å PDB-7alc: human GCH-GFRP stimulatory complex 手法: X-RAY DIFFRACTION / 解像度: 1.726 Å
化合物	ChemComp-ZN: Unknown entry ChemComp-PHE: PHENYLALANINE / フェニルアラニン ChemComp-8GT: 8-OXO-GUANOSINE-5'-TRIPHOSPHATE / 8-オキソ-GTP ChemComp-HBI: 7,8-DIHYDROBIOPTERIN / 7,8-ジヒドロビオプテリン ChemComp-QBQ: 7-deaza-GTP / 7-デアザ-GTP ChemComp-HOH: WATER ChemComp-QBK: 5-azanyl-[1,3]thiazolo[5,4-d]pyrimidine-2,7-dione ChemComp-K: Unknown entry / カリウムカチオン ChemComp-5RW: 2-azanyl-8-[(4-fluorophenyl)methylsulfanyl]-1,7-dihydropurin-6-one ChemComp-NA: Unknown entry / ナトリウムカチオン
由来	homo sapiens (ヒト)
キーワード	HYDROLASE / GTP cyclohydrolase GFTP / I / EC:3.5.4.16 / Tetrahydrobiopterin (BH4) synthesis / Cytosol / Zinc Ion Binding / Hydrolase Activity / Metal Ion Binding / Nucleotide Binding / allosteric enzyme / substrate analogue bound / allosteric inhibited / GTP cyclohydrolase I / allosteric inhibitor / PROTEIN BINDING / GTP cyclohydrolase 1 feedback regulatory protein / regulatory protein / L-phenylalanine binding (Phe) synthesis allosteric regulation / GTP cyclohydrolase 1 / GTPCH1 / GTP cyclohydrolase I regulatory protein / GFRP / allosteric regulation / complex / allosteric regulator