4htx

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Crystal structure of PDE2 catalytic domain in complex with BAY60-7550

Structural highlights

4htx is a 4 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 1.9Å
Ligands:19F, MG, ZN
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

PDE2A_HUMAN Cyclic nucleotide phosphodiesterase with a dual-specificity for the second messengers cAMP and cGMP, which are key regulators of many important physiological processes.[1] [2]

Publication Abstract from PubMed

To better understand the structural origins of inhibitor selectivity of human phosphodieasterase families (PDEs 1-11), here we report the X-ray crystal structure of PDE2 in complex with a highly selective, nanomolar inhibitor (BAY60-7550) at 1.9 A resolution, and the structure of apo PDE2 at 2.0 A resolution. The crystal structures reveal that the inhibitor binds to the PDE2 active site by using not only the conserved glutamine-switch mechanism for substrate binding, but also a binding-induced, hydrophobic pocket that was not reported previously. In silico affinity profiling by molecular docking indicates that the inhibitor binding to this pocket contributes significantly to the binding affinity and thereby improves the inhibitor selectivity for PDE2. Our results highlight a structure-based design strategy that exploits the potential binding-induced pockets to achieve higher selectivity in the PDE inhibitor development.

X-ray Crystal Structure of Phosphodiesterase 2 in Complex with a Highly Selective, Nanomolar Inhibitor Reveals a Binding-Induced Pocket Important for Selectivity.,Zhu J, Yang Q, Dai D, Huang Q J Am Chem Soc. 2013 Aug 14;135(32):11708-11. doi: 10.1021/ja404449g. Epub 2013, Aug 2. PMID:23899287[3]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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Citations
5 reviews cite this structure
In Search of Enzymes with a Role in 3', 5'-Cyclic Guanosine Monophosphate Metabolism in Plants.
Gross et al. (2016)
4 more
10 other articles
No citations found

See Also

References

  1. ↑ Iffland A, Kohls D, Low S, Luan J, Zhang Y, Kothe M, Cao Q, Kamath AV, Ding YH, Ellenberger T. Structural determinants for inhibitor specificity and selectivity in PDE2A using the wheat germ in vitro translation system. Biochemistry. 2005 Jun 14;44(23):8312-25. PMID:15938621 doi:10.1021/bi047313h
  2. ↑ Pandit J, Forman MD, Fennell KF, Dillman KS, Menniti FS. Mechanism for the allosteric regulation of phosphodiesterase 2A deduced from the X-ray structure of a near full-length construct. Proc Natl Acad Sci U S A. 2009 Oct 14. PMID:19828435
  3. ↑ Zhu J, Yang Q, Dai D, Huang Q. X-ray Crystal Structure of Phosphodiesterase 2 in Complex with a Highly Selective, Nanomolar Inhibitor Reveals a Binding-Induced Pocket Important for Selectivity. J Am Chem Soc. 2013 Aug 14;135(32):11708-11. doi: 10.1021/ja404449g. Epub 2013, Aug 2. PMID:23899287 doi:10.1021/ja404449g

Contents


PDB ID 4htx

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