4LM1

Crystal structure of PDE10A2 with fragment ZT450

4LM1 の概要

• エントリーDOI: 10.2210/pdb4lm1/pdb
• 関連するPDBエントリー: 4LKQ 4LLJ 4LLL 4LLP 4LLX 4LM0 4LM2 4LM3 4LM4
• 分子名称: cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A, 5-nitroquinoline, NICKEL (II) ION, ... (4 entities in total)
• 機能のキーワード: fragment screening, hydrolase, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Cytoplasm: Q9Y233
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 79367.41

構造登録者

Sridhar, V.,Badger, J.,Logan, C.,Chie-Leon, B.,Nienaber, V. (登録日: 2013-07-09, 公開日: 2014-02-26, 最終更新日: 2023-09-20)

主引用文献

Recht, M.I.,Sridhar, V.,Badger, J.,Bounaud, P.Y.,Logan, C.,Chie-Leon, B.,Nienaber, V.,Torres, F.E.
Identification and Optimization of PDE10A Inhibitors Using Fragment-Based Screening by Nanocalorimetry and X-ray Crystallography.
J Biomol Screen, 19:497-507, 2014

PubMed Abstract: Fragment-based lead discovery (FBLD) is a technique in which small, low-complexity chemical fragments of 6 to 15 heavy atoms are screened for binding to or inhibiting activity of the target. Hits are then linked and/or elaborated into tightly binding ligands, ideally yielding early lead compounds for drug discovery. Calorimetry provides a label-free method to assay binding and enzymatic activity that is unaffected by the spectroscopic properties of the sample. Conventional microcalorimetry is hampered by requiring large quantities of reagents and long measurement times. Nanocalorimeters can overcome these limitations of conventional isothermal titration calorimetry. Here we use enthalpy arrays, which are arrays of nanocalorimeters, to perform an enzyme activity-based fragment screen for competitive inhibitors of phosphodiesterase 10A (PDE10A). Two dozen fragments with KI <2 mM were identified and moved to crystal soaking trials. All soak experiments yielded high-resolution diffraction, with two-thirds of the fragments yielding high-resolution co-crystal structures with PDE10A. The structural information was used to elaborate fragment hits, yielding leads with KI <1 µM. This study shows how array calorimetry can be used as a prescreening method for fragment-based lead discovery with enzyme targets and paired successfully with an X-ray crystallography secondary screen.

PubMed: 24375910
DOI: 10.1177/1087057113516493

実験手法

X-RAY DIFFRACTION (1.6 Å)