3w5e: Difference between revisions

Revision as of 05:22, 3 August 2022

Crystal structure of phosphodiesterase 4B in complex with compound 31e

Structural highlights

3w5e is a 2 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	CA, NVW, ZN
Gene:	DPDE4, PDE4B (HUMAN)
Activity:	3',5'-cyclic-nucleotide phosphodiesterase, with EC number 3.1.4.17
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

[PDE4B_HUMAN] Hydrolyzes the second messenger cAMP, which is a key regulator of many important physiological processes. May be involved in mediating central nervous system effects of therapeutic agents ranging from antidepressants to antiasthmatic and anti-inflammatory agents.^[1] ^[2]

Publication Abstract from PubMed

2-Phenyl-4-piperidinyl-6,7-dihydrothieno[3,4-d]pyrimidine derivative (2) was found to be a new PDE4 inhibitor with moderate PDE4B activity (IC50=150nM). A number of derivatives with a variety of 4-amino substituents and fused bicyclic pyrimidines were synthesized. Among these, 5,5-dioxo-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine derivative (18) showed potent PDE4B inhibitory activity (IC50=25 nM). Finally, N-propylacetamide derivative (31b) was determined as a potent inhibitor for both PDE4B (IC50=7.5nM) and TNF-alpha production in mouse splenocytes (IC50=9.8nM) and showed good in vivo anti-inflammatory activity in the LPS-induced lung inflammation model in mice (ID50=18mg/kg). The binding mode of the new inhibitor (31e) in the catalytic site of PDE4B is presented based on an X-ray crystal structure of the ligand-enzyme complex.

Identification of the fused bicyclic 4-amino-2-phenylpyrimidine derivatives as novel and potent PDE4 inhibitors.,Goto T, Shiina A, Yoshino T, Mizukami K, Hirahara K, Suzuki O, Sogawa Y, Takahashi T, Mikkaichi T, Nakao N, Takahashi M, Hasegawa M, Sasaki S Bioorg Med Chem Lett. 2013 Jun 1;23(11):3325-8. doi: 10.1016/j.bmcl.2013.03.104. , Epub 2013 Apr 4. PMID:23602400^[3]

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

References

↑ Xu RX, Hassell AM, Vanderwall D, Lambert MH, Holmes WD, Luther MA, Rocque WJ, Milburn MV, Zhao Y, Ke H, Nolte RT. Atomic structure of PDE4: insights into phosphodiesterase mechanism and specificity. Science. 2000 Jun 9;288(5472):1822-5. PMID:10846163
↑ Xu RX, Rocque WJ, Lambert MH, Vanderwall DE, Luther MA, Nolte RT. Crystal structures of the catalytic domain of phosphodiesterase 4B complexed with AMP, 8-Br-AMP, and rolipram. J Mol Biol. 2004 Mar 19;337(2):355-65. PMID:15003452 doi:https://dx.doi.org/10.1016/j.jmb.2004.01.040
↑ Goto T, Shiina A, Yoshino T, Mizukami K, Hirahara K, Suzuki O, Sogawa Y, Takahashi T, Mikkaichi T, Nakao N, Takahashi M, Hasegawa M, Sasaki S. Identification of the fused bicyclic 4-amino-2-phenylpyrimidine derivatives as novel and potent PDE4 inhibitors. Bioorg Med Chem Lett. 2013 Jun 1;23(11):3325-8. doi: 10.1016/j.bmcl.2013.03.104. , Epub 2013 Apr 4. PMID:23602400 doi:10.1016/j.bmcl.2013.03.104

Proteopedia Page Contributors and Editors (what is this?)

OCA

[1] Xu RX, Hassell AM, Vanderwall D, Lambert MH, Holmes WD, Luther MA, Rocque WJ, Milburn MV, Zhao Y, Ke H, Nolte RT. Atomic structure of PDE4: insights into phosphodiesterase mechanism and specificity. Science. 2000 Jun 9;288(5472):1822-5. PMID:10846163

[2] Xu RX, Rocque WJ, Lambert MH, Vanderwall DE, Luther MA, Nolte RT. Crystal structures of the catalytic domain of phosphodiesterase 4B complexed with AMP, 8-Br-AMP, and rolipram. J Mol Biol. 2004 Mar 19;337(2):355-65. PMID:15003452 doi:https://dx.doi.org/10.1016/j.jmb.2004.01.040

[3] Goto T, Shiina A, Yoshino T, Mizukami K, Hirahara K, Suzuki O, Sogawa Y, Takahashi T, Mikkaichi T, Nakao N, Takahashi M, Hasegawa M, Sasaki S. Identification of the fused bicyclic 4-amino-2-phenylpyrimidine derivatives as novel and potent PDE4 inhibitors. Bioorg Med Chem Lett. 2013 Jun 1;23(11):3325-8. doi: 10.1016/j.bmcl.2013.03.104. , Epub 2013 Apr 4. PMID:23602400 doi:10.1016/j.bmcl.2013.03.104

[1]

[2]

[3]

@@ Line 1: / Line 1: @@
 ==Crystal structure of phosphodiesterase 4B in complex with compound 31e==
-<StructureSection load='3w5e' size='340' side='right' caption='[[3w5e]], [[Resolution|resolution]] 2.30&Aring;' scene=''>
+<StructureSection load='3w5e' size='340' side='right'caption='[[3w5e]], [[Resolution|resolution]] 2.30&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[3w5e]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3W5E OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3W5E FirstGlance]. <br>
+<table><tr><td colspan='2'>[[3w5e]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3W5E OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3W5E FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=NVW:N-TERT-BUTYL-2-{4-[(5,5-DIOXIDO-2-PHENYL-7,8-DIHYDRO-6H-THIOPYRANO[3,2-D]PYRIMIDIN-4-YL)AMINO]PHENYL}ACETAMIDE'>NVW</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
+</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=NVW:N-TERT-BUTYL-2-{4-[(5,5-DIOXIDO-2-PHENYL-7,8-DIHYDRO-6H-THIOPYRANO[3,2-D]PYRIMIDIN-4-YL)AMINO]PHENYL}ACETAMIDE'>NVW</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
-<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">DPDE4, PDE4B ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
+<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">DPDE4, PDE4B ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
-<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/3',5'-cyclic-nucleotide_phosphodiesterase 3',5'-cyclic-nucleotide phosphodiesterase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.1.4.17 3.1.4.17] </span></td></tr>
+<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/3',5'-cyclic-nucleotide_phosphodiesterase 3',5'-cyclic-nucleotide phosphodiesterase], with EC number [https://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.1.4.17 3.1.4.17] </span></td></tr>
-<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3w5e FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3w5e OCA], [http://pdbe.org/3w5e PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=3w5e RCSB], [http://www.ebi.ac.uk/pdbsum/3w5e PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=3w5e ProSAT]</span></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=3w5e FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3w5e OCA], [https://pdbe.org/3w5e PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3w5e RCSB], [https://www.ebi.ac.uk/pdbsum/3w5e PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3w5e ProSAT]</span></td></tr>
 </table>
 == Function ==
-[[http://www.uniprot.org/uniprot/PDE4B_HUMAN PDE4B_HUMAN]] Hydrolyzes the second messenger cAMP, which is a key regulator of many important physiological processes. May be involved in mediating central nervous system effects of therapeutic agents ranging from antidepressants to antiasthmatic and anti-inflammatory agents.<ref>PMID:10846163</ref> <ref>PMID:15003452</ref>
+[[https://www.uniprot.org/uniprot/PDE4B_HUMAN PDE4B_HUMAN]] Hydrolyzes the second messenger cAMP, which is a key regulator of many important physiological processes. May be involved in mediating central nervous system effects of therapeutic agents ranging from antidepressants to antiasthmatic and anti-inflammatory agents.<ref>PMID:10846163</ref> <ref>PMID:15003452</ref>
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==
@@ Line 20: / Line 20: @@
 </div>
 <div class="pdbe-citations 3w5e" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[Phosphodiesterase 3D structures|Phosphodiesterase 3D structures]]
 == References ==
 <references/>
@@ Line 26: / Line 29: @@
 [[Category: 3',5'-cyclic-nucleotide phosphodiesterase]]
 [[Category: Human]]
+[[Category: Large Structures]]
 [[Category: Hanzawa, H]]
 [[Category: Takahashi, M]]

3w5e: Difference between revisions

Revision as of 05:22, 3 August 2022

Crystal structure of phosphodiesterase 4B in complex with compound 31e

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

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