9lo7

The crystal structure of PDE4D with 2317b

Structural highlights

9lo7 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 2.2000625Å
Ligands:	A1EKX, 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

Psoriasis is a complex chronic inflammatory disease that severely affects the quality of life of patients. However, current medications could only control the symptoms but not cure psoriasis with unmet medical needs. Herein, structure-based optimizations of natural product moracin M (IC(50) of 2.9 muM) led to a novel PDE4 inhibitor L30 with greatly improved potency (IC(50) of 8.6 nM) and remarkable selectivity across other PDEs families (>201-fold). The binding pattern of L30 with PDE4 revealed by cocrystal structure was different from that of roflumilast. Besides, L30 could effectively inhibit the release of inflammatory cytokines and chemokines in Raw264.7 and HaCaT cell lines. Furthermore, topical administration of L30 exhibited significant therapeutic effects in an imiquimod-induced psoriasis mouse model. These findings highlighted the potential of PDE4 inhibitor L30 as a novel lead for the treatment of psoriasis.

Structure-Based Optimization of Moracin M as Potent and Selective PDE4 Inhibitors with Antipsoriasis Effects.,Zhang F, Zheng T, Wang X, Chen Y, Zhang F, Liu X, Wang S, Yang G, Xie S, Wu Q, Xu C, Zhou Q, Wu D, Luo HB, Huang YY J Med Chem. 2025 Mar 11. doi: 10.1021/acs.jmedchem.5c00266. PMID:40066994^[4]

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

References

↑ 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
↑ 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:https://dx.doi.org/10.1016/j.molcel.2004.07.005
↑ 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:https://dx.doi.org/10.1016/j.str.2004.10.004
↑ Zhang F, Zheng T, Wang X, Chen Y, Zhang F, Liu X, Wang S, Yang G, Xie S, Wu Q, Xu C, Zhou Q, Wu D, Luo HB, Huang YY. Structure-Based Optimization of Moracin M as Potent and Selective PDE4 Inhibitors with Antipsoriasis Effects. J Med Chem. 2025 Mar 11. PMID:40066994 doi:10.1021/acs.jmedchem.5c00266

Proteopedia Page Contributors and Editors (what is this?)

OCA

[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:https://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:https://dx.doi.org/10.1016/j.str.2004.10.004

[4] Zhang F, Zheng T, Wang X, Chen Y, Zhang F, Liu X, Wang S, Yang G, Xie S, Wu Q, Xu C, Zhou Q, Wu D, Luo HB, Huang YY. Structure-Based Optimization of Moracin M as Potent and Selective PDE4 Inhibitors with Antipsoriasis Effects. J Med Chem. 2025 Mar 11. PMID:40066994 doi:10.1021/acs.jmedchem.5c00266

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9lo7

The crystal structure of PDE4D with 2317b

Structural highlights

Disease

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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