6AKR

Crystal structure of the PDE4D catalytic domain in complex with osthole

Summary for 6AKR

• Entry DOI: 10.2210/pdb6akr/pdb
• Descriptor: cAMP-specific 3',5'-cyclic phosphodiesterase 4D, ZINC ION, 7-methoxy-8-(3-methylbut-2-enyl)chromen-2-one, ... (4 entities in total)
• Functional Keywords: phosphodiesterase 4d, hydrolase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 4
• Total formula weight: 168733.38

Authors

Wang, S.,Huo, Y.W.,Xie, Y. (deposition date: 2018-09-03, release date: 2020-02-12, Last modification date: 2023-11-22)

Primary citation

Wang, S.,Xie, Y.,Huo, Y.W.,Li, Y.,Abel, P.W.,Jiang, H.,Zou, X.,Jiao, H.Z.,Kuang, X.,Wolff, D.W.,Huang, Y.G.,Casale, T.B.,Panettieri Jr., R.A.,Wei, T.,Cao, Z.,Tu, Y.
Airway relaxation mechanisms and structural basis of osthole for improving lung function in asthma.
Sci.Signal., 13:-, 2020

PubMed Abstract: Overuse of β2-adrenoceptor agonist bronchodilators evokes receptor desensitization, decreased efficacy, and an increased risk of death in asthma patients. Bronchodilators that do not target β2-adrenoceptors represent a critical unmet need for asthma management. Here, we characterize the utility of osthole, a coumarin derived from a traditional Chinese medicine, in preclinical models of asthma. In mouse precision-cut lung slices, osthole relaxed preconstricted airways, irrespective of β2-adrenoceptor desensitization. Osthole administered in murine asthma models attenuated airway hyperresponsiveness, a hallmark of asthma. Osthole inhibited phosphodiesterase 4D (PDE4D) activity to amplify autocrine prostaglandin E signaling in airway smooth muscle cells that eventually triggered cAMP/PKA-dependent relaxation of airways. The crystal structure of the PDE4D complexed with osthole revealed that osthole bound to the catalytic site to prevent cAMP binding and hydrolysis. Together, our studies elucidate a specific molecular target and mechanism by which osthole induces airway relaxation. Identification of osthole binding sites on PDE4D will guide further development of bronchodilators that are not subject to tachyphylaxis and would thus avoid β2-adrenoceptor agonist resistance.

PubMed: 33234690
DOI: 10.1126/scisignal.aax0273

Experimental method

X-RAY DIFFRACTION (2.326 Å)