6kk0

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Crystal structure of PDE4D catalytic domain complexed with compound 4e

Structural highlights

6kk0 is a 2 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 2.2000875Å
Ligands:M36, MG, ZN
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

PDE4D_HUMAN Note=Genetic variations in PDE4D might be associated with susceptibility to stroke. PubMed:17006457 states that association with stroke has to be considered with caution. Defects in PDE4D are the cause of acrodysostosis type 2, with or without hormone resistance (ACRDYS2) [MIM:614613. ACRDYS2 is a pleiotropic disorder characterized by skeletal, endocrine, and neurological abnormalities. Skeletal features include brachycephaly, midface hypoplasia with a small upturned nose, brachydactyly, and lumbar spinal stenosis. Endocrine abnormalities include hypothyroidism and hypogonadism in males and irregular menses in females. Developmental disability is a common finding but is variable in severity and can be associated with significant behavioral problems.[1]

Function

PDE4D_HUMAN Hydrolyzes the second messenger cAMP, which is a key regulator of many important physiological processes.[2] [3]

Publication Abstract from PubMed

To validate PDE4 inhibitors as novel therapeutic agents against vascular dementia (VaD), 25 derivatives were discovered from the natural inhibitor alpha-mangostin (IC50 = 1.31 muM). Hit-to-lead optimization identified a novel and selective PDE4 inhibitor 4e (IC50 = 17 nM), which adopted a different binding pattern from PDE4 inhibitors roflumilast and rolipram. Oral administration of 4e at a dose of 10 mg/kg exhibited remarkable therapeutic effects in a VaD model and did not cause emesis to beagle dogs, indicating its potential as a novel anti-VaD agent.

Discovery and Optimization of alpha-Mangostin Derivatives as Novel PDE4 Inhibitors for the Treatment of Vascular Dementia.,Liang J, Huang YY, Zhou Q, Gao Y, Li Z, Wu D, Yu S, Guo L, Chen Z, Huang L, Liang SH, He X, Wu R, Luo HB J Med Chem. 2020 Mar 12. doi: 10.1021/acs.jmedchem.0c00060. PMID:32115956[4]

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

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Citations
1 reviews cite this structure
Phosphodiesterase-4 Inhibition in Parkinson's Disease: Molecular Insights and Therapeutic Potential.
Roy et al. (2023)
0 more
4 other articles
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See Also

References

  1. ↑ Michot C, Le Goff C, Goldenberg A, Abhyankar A, Klein C, Kinning E, Guerrot AM, Flahaut P, Duncombe A, Baujat G, Lyonnet S, Thalassinos C, Nitschke P, Casanova JL, Le Merrer M, Munnich A, Cormier-Daire V. Exome sequencing identifies PDE4D mutations as another cause of acrodysostosis. Am J Hum Genet. 2012 Apr 6;90(4):740-5. doi: 10.1016/j.ajhg.2012.03.003. Epub, 2012 Mar 29. PMID:22464250 doi:10.1016/j.ajhg.2012.03.003
  2. ↑ Zhang KY, Card GL, Suzuki Y, Artis DR, Fong D, Gillette S, Hsieh D, Neiman J, West BL, Zhang C, Milburn MV, Kim SH, Schlessinger J, Bollag G. A glutamine switch mechanism for nucleotide selectivity by phosphodiesterases. Mol Cell. 2004 Jul 23;15(2):279-86. PMID:15260978 doi:http://dx.doi.org/10.1016/j.molcel.2004.07.005
  3. ↑ Card GL, England BP, Suzuki Y, Fong D, Powell B, Lee B, Luu C, Tabrizizad M, Gillette S, Ibrahim PN, Artis DR, Bollag G, Milburn MV, Kim SH, Schlessinger J, Zhang KY. Structural basis for the activity of drugs that inhibit phosphodiesterases. Structure. 2004 Dec;12(12):2233-47. PMID:15576036 doi:http://dx.doi.org/10.1016/j.str.2004.10.004
  4. ↑ Liang J, Huang YY, Zhou Q, Gao Y, Li Z, Wu D, Yu S, Guo L, Chen Z, Huang L, Liang SH, He X, Wu R, Luo HB. Discovery and Optimization of alpha-Mangostin Derivatives as Novel PDE4 Inhibitors for the Treatment of Vascular Dementia. J Med Chem. 2020 Mar 12. doi: 10.1021/acs.jmedchem.0c00060. PMID:32115956 doi:http://dx.doi.org/10.1021/acs.jmedchem.0c00060

Contents


PDB ID 6kk0

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OCA

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