4JIB

Crystal structure of of PDE2-inhibitor complex

Summary for 4JIB

• Entry DOI: 10.2210/pdb4jib/pdb
• Related: 3ITM
• Descriptor: cGMP-dependent 3',5'-cyclic phosphodiesterase, ZINC ION, MAGNESIUM ION, ... (5 entities in total)
• Functional Keywords: hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Isoform PDE2A3: Cell membrane ; Lipid-anchor . Isoform PDE2A2: Mitochondrion matrix . Isoform PDE2A1: Cytoplasm . Isoform 5: Mitochondrion : O00408
• Total number of polymer chains: 4
• Total formula weight: 162941.29

Authors

Pandit, J. (deposition date: 2013-03-05, release date: 2013-05-01, Last modification date: 2024-02-28)

Primary citation

Plummer, M.S.,Cornicelli, J.,Roark, H.,Skalitzky, D.J.,Stankovic, C.J.,Bove, S.,Pandit, J.,Goodman, A.,Hicks, J.,Shahripour, A.,Beidler, D.,Lu, X.K.,Sanchez, B.,Whitehead, C.,Sarver, R.,Braden, T.,Gowan, R.,Shen, X.Q.,Welch, K.,Ogden, A.,Sadagopan, N.,Baum, H.,Miller, H.,Banotai, C.,Spessard, C.,Lightle, S.
Discovery of potent, selective, bioavailable phosphodiesterase 2 (PDE2) inhibitors active in an osteoarthritis pain model, Part I: Transformation of selective pyrazolodiazepinone phosphodiesterase 4 (PDE4) inhibitors into selective PDE2 inhibitors.
Bioorg.Med.Chem.Lett., 23:3438-3442, 2013

PubMed Abstract: We identified potent, selective PDE2 inhibitors by optimizing residual PDE2 activity in a series of PDE4 inhibitors, while simultaneously minimizing PDE4 activity. These newly designed PDE2 inhibitors bind to the PDE2 enzyme in a cGMP-like mode in contrast to the cAMP-like binding mode found in PDE4. Structure activity relationship studies coupled with an inhibitor bound crystal structure in the active site of the catalytic domain of PDE2 identified structural features required to minimize PDE4 inhibition while simultaneously maximizing PDE2 inhibition.

PubMed: 23582272
DOI: 10.1016/j.bmcl.2013.03.072

Experimental method

X-RAY DIFFRACTION (1.72 Å)