6NJH

Crystal Structure of the PDE4D Catalytic Domain and UCR2 Regulatory Helix with T-48

Summary for 6NJH

• Entry DOI: 10.2210/pdb6njh/pdb
• Descriptor: cAMP-specific 3',5'-cyclic phosphodiesterase 4D, ZINC ION, MAGNESIUM ION, ... (5 entities in total)
• Functional Keywords: pde4d, camp-specific 3'5'-cyclic phosphodiesterase 4d, ucr2, camp, hydrolase, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 4
• Total formula weight: 172251.00

Authors

Fox III, D.,Fairman, J.W.,Gurney, M.E. (deposition date: 2019-01-03, release date: 2019-05-08, Last modification date: 2024-03-13)

Primary citation

Gurney, M.E.,Nugent, R.A.,Mo, X.,Sindac, J.A.,Hagen, T.J.,Fox III, D.,O'Donnell, J.M.,Zhang, C.,Xu, Y.,Zhang, H.T.,Groppi, V.E.,Bailie, M.,White, R.E.,Romero, D.L.,Vellekoop, A.S.,Walker, J.R.,Surman, M.D.,Zhu, L.,Campbell, R.F.
Design and Synthesis of Selective Phosphodiesterase 4D (PDE4D) Allosteric Inhibitors for the Treatment of Fragile X Syndrome and Other Brain Disorders.
J.Med.Chem., 62:4884-4901, 2019

PubMed Abstract: Novel pyridine- and pyrimidine-based allosteric inhibitors are reported that achieve PDE4D subtype selectivity through recognition of a single amino acid difference on a key regulatory domain, known as UCR2, that opens and closes over the catalytic site for cAMP hydrolysis. The design and optimization of lead compounds was based on iterative analysis of X-ray crystal structures combined with metabolite identification. Selectivity for the activated, dimeric form of PDE4D provided potent memory enhancing effects in a mouse model of novel object recognition with improved tolerability and reduced vascular toxicity over earlier PDE4 inhibitors that lack subtype selectivity. The lead compound, 28 (BPN14770), has entered midstage, human phase 2 clinical trials for the treatment of Fragile X Syndrome.

PubMed: 31013090
DOI: 10.1021/acs.jmedchem.9b00193

Experimental method

X-RAY DIFFRACTION (2.15 Å)