3V8P

Crystal structure of NAD kinase 1 from Listeria monocytogenes in complex with a new di-adenosine inhibitor formed in situ

3V8P の概要

• エントリーDOI: 10.2210/pdb3v8p/pdb
• 関連するPDBエントリー: 2I2C 3V7V 3V7W 3V7Y 3V80 3V8M 3V8N 3V8Q 3V8R
• 分子名称: Probable inorganic polyphosphate/ATP-NAD kinase 1, CITRIC ACID, 2-[6-azanyl-9-[(2R,3R,4S,5R)-5-[[(azanylidene-$l^{4}-azanylidene)amino]methyl]-3,4-bis(oxidanyl)oxolan-2-yl]purin-8-yl]sulfanyl-N-[[(2R,3S,4R,5R)-5-(6-azanyl-8-bromanyl-purin-9-yl)-3,4-bis(oxidanyl)oxolan-2-yl]methyl]ethanamide, ... (4 entities in total)
• 機能のキーワード: ligand-screening by crystallography, two-domain kinase, inorganic polyphosphate/atp-nad kinase 1, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 由来する生物種: Listeria monocytogenes
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 31946.89

構造登録者

Gelin, M.,Poncet-Montange, G.,Assairi, L.,Morellato, L.,Huteau, V.,Dugu, L.,Dussurget, O.,Pochet, S.,Labesse, G. (登録日: 2011-12-23, 公開日: 2012-03-14, 最終更新日: 2024-05-15)

主引用文献

Gelin, M.,Poncet-Montange, G.,Assairi, L.,Morellato, L.,Huteau, V.,Dugue, L.,Dussurget, O.,Pochet, S.,Labesse, G.
Screening and In Situ Synthesis Using Crystals of a NAD Kinase Lead to a Potent Antistaphylococcal Compound.
Structure, 20:1107-1117, 2012

PubMed Abstract: Making new ligands for a given protein by in situ ligation of building blocks (or fragments) is an attractive method. However, it suffers from inherent limitations, such as the limited number of available chemical reactions and the low information content of usual chemical library deconvolution. Here, we describe a focused screening of adenosine derivatives using X-ray crystallography. We discovered an unexpected and biocompatible chemical reactivity and have simultaneously identified the mode of binding of the resulting products. We observed that the NAD kinase from Listeria monocytogenes (LmNADK1) can promote amide formation between 5'-amino-5'-deoxyadenosine and carboxylic acid groups. This unexpected reactivity allowed us to bridge in situ two adenosine derivatives to fully occupy the active NAD site. This guided the design of a close analog showing micromolar inhibition of two human pathogenic NAD kinases and potent bactericidal activity against Staphylococcus aureus in vitro.

PubMed: 22608967
DOI: 10.1016/j.str.2012.03.024

実験手法

X-RAY DIFFRACTION (2.2901 Å)