3TVX

The structure of PDE4A with pentoxifylline at 2.84A resolution

3TVX の概要

• エントリーDOI: 10.2210/pdb3tvx/pdb
• 分子名称: cAMP-specific 3',5'-cyclic phosphodiesterase 4A, ZINC ION, MAGNESIUM ION, ... (5 entities in total)
• 機能のキーワード: hydrolase, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Isoform 1: Cytoplasm, perinuclear region. Isoform 2: Cytoplasm, perinuclear region. Isoform 4: Membrane; Peripheral membrane protein. Isoform 6: Cytoplasm, perinuclear region. Isoform 7: Cytoplasm: P27815
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 78472.37

構造登録者

Badger, J.,Sridhar, V. (登録日: 2011-09-20, 公開日: 2012-01-25, 最終更新日: 2023-09-13)

主引用文献

Recht, M.I.,Sridhar, V.,Badger, J.,Hernandez, L.,Chie-Leon, B.,Nienaber, V.,Torres, F.E.
Fragment-Based Screening for Inhibitors of PDE4A Using Enthalpy Arrays and X-ray Crystallography.
J Biomol Screen, 17:469-480, 2012

PubMed Abstract: Fragment-based screening has typically relied on X-ray or nuclear magnetic resonance methods to identify low-affinity ligands that bind to therapeutic targets. These techniques are expensive in terms of material and time, so it useful to have a higher throughput method to reliably prescreen a fragment library to identify a subset of compounds for structural analysis. 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 have used enthalpy arrays, which are arrays of nanocalorimeters, to perform an enzyme activity-based fragment screen for competitive inhibitors of phosphodiesterase 4A (PDE4A). Several inhibitors with K ( I ) <2 mM were identified and moved to X-ray crystallization trials. Although the co-crystals did not yield high-resolution data, evidence of binding was observed, and the chemical structures of the hits were consistent with motifs of known PDE4 inhibitors. This study shows how array calorimetry can be used as a prescreening method for fragment-based lead discovery with enzyme targets and provides a list of candidate fragments for inhibition of PDE4A.

PubMed: 22223051
DOI: 10.1177/1087057111430987

実験手法

X-RAY DIFFRACTION (2.84 Å)