9lrp: Difference between revisions

Latest revision as of 08:58, 11 March 2026

The crystal structure of PDE4D with 13c

Structural highlights

9lrp 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 2.1000073Å
Ligands:	A1ELB, 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

Phosphodiesterase 4 (PDE4) has been validated as a promising therapeutic target for idiopathic pulmonary fibrosis (IPF), a devastating interstitial lung disease lacking really effective therapeutic drugs, particularly exacerbated in the post-COVID-19 era. Herein, we reported the discovery of 13c, a novel pyrazolo[1,5-a]pyrimidine-based PDE4 inhibitor, via an innovative artificial intelligence (AI)-driven virtual screening approach integrated with structure-based design. The cocrystal analysis of PDE4-13c elucidated the structural basis of its high affinity, revealing that the unique "halogen-binding and metal-coordination" synergistic network significantly influenced PDE4 inhibitory activity, which resulted in a 268-fold potency enhancement (IC(50) = 2.7 nM) over hit T3700 (IC(50) = 725 nM). Notably, 13c exhibited remarkable hepatic microsomal stability (RLM(1/2) = 141.4 min). Furthermore, 13c exhibited remarkable antifibrotic activity in vitro and significantly attenuated bleomycin-induced pulmonary fibrosis in vivo, highlighting its potential as a novel PDE4 inhibitor for IPF.

Artificial Intelligence-Driven Discovery of Pyrazolo[1,5-a]pyrimidine Derivatives as Novel Phosphodiesterase 4 Inhibitors for Treating Idiopathic Pulmonary Fibrosis.,Li Z, Huan W, Liu X, Zhang K, Wang X, Huang Y, Zhou Q, Huang S, Sang Z, Luo HB J Med Chem. 2025 Nov 27;68(22):24436-24455. doi: 10.1021/acs.jmedchem.5c02407. , Epub 2025 Nov 18. PMID:41252469^[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
↑ Li Z, Huan W, Liu X, Zhang K, Wang X, Huang Y, Zhou Q, Huang S, Sang Z, Luo HB. Artificial Intelligence-Driven Discovery of Pyrazolo[1,5-a]pyrimidine Derivatives as Novel Phosphodiesterase 4 Inhibitors for Treating Idiopathic Pulmonary Fibrosis. J Med Chem. 2025 Nov 27;68(22):24436-24455. PMID:41252469 doi:10.1021/acs.jmedchem.5c02407

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] Li Z, Huan W, Liu X, Zhang K, Wang X, Huang Y, Zhou Q, Huang S, Sang Z, Luo HB. Artificial Intelligence-Driven Discovery of Pyrazolo[1,5-a]pyrimidine Derivatives as Novel Phosphodiesterase 4 Inhibitors for Treating Idiopathic Pulmonary Fibrosis. J Med Chem. 2025 Nov 27;68(22):24436-24455. PMID:41252469 doi:10.1021/acs.jmedchem.5c02407

[1]

[2]

[3]

[4]

@@ Line 1: / Line 1: @@
-'''Unreleased structure'''
-The entry 9lrp is ON HOLD  until Paper Publication
+==The crystal structure of PDE4D with 13c==
+<StructureSection load='9lrp' size='340' side='right'caption='[[9lrp]], [[Resolution|resolution]] 2.10&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[9lrp]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=9LRP OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=9LRP FirstGlance]. <br>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.1000073&#8491;</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=A1ELB:4-[[7-azanyl-6-bromanyl-3-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrimidin-5-yl]amino]-~{N}-oxidanyl-butanamide'>A1ELB</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=9lrp FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=9lrp OCA], [https://pdbe.org/9lrp PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=9lrp RCSB], [https://www.ebi.ac.uk/pdbsum/9lrp PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=9lrp ProSAT]</span></td></tr>
+</table>
+== Disease ==
+[https://www.uniprot.org/uniprot/PDE4D_HUMAN 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:[https://omim.org/entry/614613 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.<ref>PMID:22464250</ref>
+== Function ==
+[https://www.uniprot.org/uniprot/PDE4D_HUMAN PDE4D_HUMAN] Hydrolyzes the second messenger cAMP, which is a key regulator of many important physiological processes.<ref>PMID:15260978</ref> <ref>PMID:15576036</ref>
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+Phosphodiesterase 4 (PDE4) has been validated as a promising therapeutic target for idiopathic pulmonary fibrosis (IPF), a devastating interstitial lung disease lacking really effective therapeutic drugs, particularly exacerbated in the post-COVID-19 era. Herein, we reported the discovery of 13c, a novel pyrazolo[1,5-a]pyrimidine-based PDE4 inhibitor, via an innovative artificial intelligence (AI)-driven virtual screening approach integrated with structure-based design. The cocrystal analysis of PDE4-13c elucidated the structural basis of its high affinity, revealing that the unique "halogen-binding and metal-coordination" synergistic network significantly influenced PDE4 inhibitory activity, which resulted in a 268-fold potency enhancement (IC(50) = 2.7 nM) over hit T3700 (IC(50) = 725 nM). Notably, 13c exhibited remarkable hepatic microsomal stability (RLM(1/2) = 141.4 min). Furthermore, 13c exhibited remarkable antifibrotic activity in vitro and significantly attenuated bleomycin-induced pulmonary fibrosis in vivo, highlighting its potential as a novel PDE4 inhibitor for IPF.
-Authors: Huang, Y.-Y., Luo, H.-B.
+Artificial Intelligence-Driven Discovery of Pyrazolo[1,5-a]pyrimidine Derivatives as Novel Phosphodiesterase 4 Inhibitors for Treating Idiopathic Pulmonary Fibrosis.,Li Z, Huan W, Liu X, Zhang K, Wang X, Huang Y, Zhou Q, Huang S, Sang Z, Luo HB J Med Chem. 2025 Nov 27;68(22):24436-24455. doi: 10.1021/acs.jmedchem.5c02407. , Epub 2025 Nov 18. PMID:41252469<ref>PMID:41252469</ref>
-Description: The crystal structure of PDE4D with 13c
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-[[Category: Unreleased Structures]]
+</div>
-[[Category: Luo, H.-B]]
+<div class="pdbe-citations 9lrp" style="background-color:#fffaf0;"></div>
-[[Category: Huang, Y.-Y]]
+== References ==
+<references/>
+__TOC__
+</StructureSection>
+[[Category: Homo sapiens]]
+[[Category: Large Structures]]
+[[Category: Huang Y-Y]]
+[[Category: Luo H-B]]

9lrp: Difference between revisions

Latest revision as of 08:58, 11 March 2026

The crystal structure of PDE4D with 13c

Structural highlights

Disease

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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