5KM1

Human Histidine Triad Nucleotide Binding Protein 1 (hHint1) GMP catalytic product complex

5KM1 の概要

• エントリーDOI: 10.2210/pdb5km1/pdb
• 関連するPDBエントリー: 3TW2 5IPB 5IPC 5IPD 5IPE 5KLY 5KLZ 5KM0 5KM2 5KM3 5KM4 5KM5 5KM6 5KM7 5KM8 5KM9 5KMA 5KMB 5KMC
• 分子名称: Histidine triad nucleotide-binding protein 1, GUANOSINE-5'-MONOPHOSPHATE, 1,2-ETHANEDIOL, ... (4 entities in total)
• 機能のキーワード: hint, histidine triad, hit, hydrolase
• 由来する生物種: Homo sapiens (Human)
• 細胞内の位置: Cytoplasm: P49773
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 28617.67

構造登録者

Maize, K.M.,Finzel, B.C. (登録日: 2016-06-26, 公開日: 2017-06-28, 最終更新日: 2023-09-27)

主引用文献

Maize, K.M.,Shah, R.,Strom, A.,Kumarapperuma, S.,Zhou, A.,Wagner, C.R.,Finzel, B.C.
A Crystal Structure Based Guide to the Design of Human Histidine Triad Nucleotide Binding Protein 1 (hHint1) Activated ProTides.
Mol. Pharm., 14:3987-3997, 2017

PubMed Abstract: Nucleotide analogues that incorporate a metabolically labile nucleoside phosphoramidate (a ProTide) have found utility as prodrugs. In humans, ProTides can be cleaved by human histidine triad nucleotide binding protein 1 (hHint1) to expose the nucleotide monophosphate. Activation by this route circumvents highly selective nucleoside kinases that limit the use of nucleosides as prodrugs. To better understand the diversity of potential substrates of hHint1, we created and studied a series of phosphoramidate nucleosides. Using a combination of enzyme kinetics, X-ray crystallography, and isothermal titration calorimetry with both wild-type and inactive mutant enzymes, we have been able to explore the energetics of substrate binding and establish a structural basis for catalytic efficiency. Diverse nucleobases are well tolerated, but portions of the ribose are needed to position substrates for catalysis. Beneficial characteristics of the amine leaving group are also revealed. Structural principles revealed by these results may be exploited to tune the rate of substrate hydrolysis to strategically alter the intracellular release of the product nucleoside monophosphate from the ProTide.

PubMed: 28968488
DOI: 10.1021/acs.molpharmaceut.7b00664

実験手法

X-RAY DIFFRACTION (1.65 Å)