3o5n

From Proteopedia

(Difference between revisions)

Revision as of 07:16, 12 May 2022

Tetrahydroquinoline carboxylates are potent inhibitors of the Shank PDZ domain, a putative target in autism disorders

Structural highlights

3o5n is a 8 chain structure with sequence from Lk3 transgenic mice. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:
Gene:	Shank3, Kiaa1650 (LK3 transgenic mice)
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

[SHAN3_MOUSE] Major scaffold postsynaptic density protein which interacts with multiple proteins and complexes to orchestrate the dendritic spine and synapse formation, maturation and maintenance. Interconnects receptors of the postsynaptic membrane including NMDA-type and metabotropic glutamate receptors via complexes with GKAP/PSD-95 and HOMER, respectively, and the actin-based cytoskeleton. Plays a role in the structural and functional organization of the dendritic spine and synaptic junction through the interaction with Arp2/3 and WAVE1 complex as well as the promotion of the F-actin clusters. By way of this control of actin dynamics, participates in the regulation of developing neurons growth cone motility and the NMDA receptor-signaling. Also modulates GRIA1 exocytosis and GRM5/MGLUR5 expression and signaling to control the AMPA and metabotropic glutamate receptor-mediated synaptic transmission and plasticity. May be required at an early stage of synapse formation and be inhibited by IGF1 to promote synapse maturation.^[1] ^[2] ^[3] ^[4]

Publication Abstract from PubMed

Shank is the central scaffolding protein of the postsynaptic density (PSD) protein complex found in cells of the central nervous system. Cellular studies indicate a prominent role of the protein in the organization of the PSD, in the development of neuronal morphology, in neuronal signaling, and in synaptic plasticity, thus linking Shank functions to the molecular basis of learning and memory. Mutations in the Shank gene have been found in several neuronal disorders including mental retardation, typical autism, and Asperger syndrome. Shank is linked to the PSD complex via its PDZ domain that binds to the C-terminus of guanylate-kinase-associated protein (GKAP). Here, small-molecule inhibitors of Shank3 PDZ domain are developed. A fluorescence polarization assay based on an identified high-affinity peptide is established, and tetrahydroquinoline carboxylates are identified as inhibitors of this protein-protein interaction. Chemical synthesis via a hetero-Diels-Alder strategy is employed for hit optimization, and structure-activity relationship studies are performed. Best hits possess K(i) values in the 10 muM range, and binding to the PDZ domain is confirmed by (1) H,(15) N HSQC NMR experiments. One of the hits crystallizes with the Shank3 PDZ domain. The structure, analyzed at a resolution of 1.85 A, reveals details of the binding mode. Finally, binding to PDZ domains of PSD-95, syntrophin, and DVL3 was studied using (1) H,(15) N HSQC NMR spectroscopy.

Discovery, Structure-Activity Relationship Studies, and Crystal Structure of Nonpeptide Inhibitors Bound to the Shank3 PDZ Domain.,Saupe J, Roske Y, Schillinger C, Kamdem N, Radetzki S, Diehl A, Oschkinat H, Krause G, Heinemann U, Rademann J ChemMedChem. 2011 May 27. doi: 10.1002/cmdc.201100094. PMID:21626699^[5]

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

References

↑ Peca J, Feliciano C, Ting JT, Wang W, Wells MF, Venkatraman TN, Lascola CD, Fu Z, Feng G. Shank3 mutant mice display autistic-like behaviours and striatal dysfunction. Nature. 2011 Apr 28;472(7344):437-42. doi: 10.1038/nature09965. Epub 2011 Mar 20. PMID:21423165 doi:http://dx.doi.org/10.1038/nature09965
↑ Wang X, McCoy PA, Rodriguiz RM, Pan Y, Je HS, Roberts AC, Kim CJ, Berrios J, Colvin JS, Bousquet-Moore D, Lorenzo I, Wu G, Weinberg RJ, Ehlers MD, Philpot BD, Beaudet AL, Wetsel WC, Jiang YH. Synaptic dysfunction and abnormal behaviors in mice lacking major isoforms of Shank3. Hum Mol Genet. 2011 Aug 1;20(15):3093-108. doi: 10.1093/hmg/ddr212. Epub 2011 May, 10. PMID:21558424 doi:http://dx.doi.org/10.1093/hmg/ddr212
↑ Raynaud F, Janossy A, Dahl J, Bertaso F, Perroy J, Varrault A, Vidal M, Worley PF, Boeckers TM, Bockaert J, Marin P, Fagni L, Homburger V. Shank3-Rich2 interaction regulates AMPA receptor recycling and synaptic long-term potentiation. J Neurosci. 2013 Jun 5;33(23):9699-715. doi: 10.1523/JNEUROSCI.2725-12.2013. PMID:23739967 doi:http://dx.doi.org/10.1523/JNEUROSCI.2725-12.2013
↑ Han K, Holder JL Jr, Schaaf CP, Lu H, Chen H, Kang H, Tang J, Wu Z, Hao S, Cheung SW, Yu P, Sun H, Breman AM, Patel A, Lu HC, Zoghbi HY. SHANK3 overexpression causes manic-like behaviour with unique pharmacogenetic properties. Nature. 2013 Nov 7;503(7474):72-7. doi: 10.1038/nature12630. Epub 2013 Oct 23. PMID:24153177 doi:http://dx.doi.org/10.1038/nature12630
↑ Saupe J, Roske Y, Schillinger C, Kamdem N, Radetzki S, Diehl A, Oschkinat H, Krause G, Heinemann U, Rademann J. Discovery, Structure-Activity Relationship Studies, and Crystal Structure of Nonpeptide Inhibitors Bound to the Shank3 PDZ Domain. ChemMedChem. 2011 May 27. doi: 10.1002/cmdc.201100094. PMID:21626699 doi:10.1002/cmdc.201100094

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 See Also
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/3o5n"

@@ Line 1: / Line 1: @@
 ==Tetrahydroquinoline carboxylates are potent inhibitors of the Shank PDZ domain, a putative target in autism disorders==
-<StructureSection load='3o5n' size='340' side='right' caption='[[3o5n]], [[Resolution|resolution]] 1.83&Aring;' scene=''>
+<StructureSection load='3o5n' size='340' side='right'caption='[[3o5n]], [[Resolution|resolution]] 1.83&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[3o5n]] is a 8 chain structure with sequence from [http://en.wikipedia.org/wiki/Lk3_transgenic_mice Lk3 transgenic mice]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3O5N OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3O5N FirstGlance]. <br>
+<table><tr><td colspan='2'>[[3o5n]] is a 8 chain structure with sequence from [https://en.wikipedia.org/wiki/Lk3_transgenic_mice Lk3 transgenic mice]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3O5N OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3O5N FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=BR0:(3AS,4R,9BR)-9-NITRO-3A,4,5,9B-TETRAHYDRO-3H-CYCLOPENTA[C]QUINOLINE-4,6-DICARBOXYLIC+ACID'>BR0</scene></td></tr>
+</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=BR0:(3AS,4R,9BR)-9-NITRO-3A,4,5,9B-TETRAHYDRO-3H-CYCLOPENTA[C]QUINOLINE-4,6-DICARBOXYLIC+ACID'>BR0</scene></td></tr>
-<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">Shank3, Kiaa1650 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=10090 LK3 transgenic mice])</td></tr>
+<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">Shank3, Kiaa1650 ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=10090 LK3 transgenic mice])</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=3o5n FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3o5n OCA], [http://pdbe.org/3o5n PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=3o5n RCSB], [http://www.ebi.ac.uk/pdbsum/3o5n PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=3o5n 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=3o5n FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3o5n OCA], [https://pdbe.org/3o5n PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3o5n RCSB], [https://www.ebi.ac.uk/pdbsum/3o5n PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3o5n ProSAT]</span></td></tr>
 </table>
 == Function ==
-[[http://www.uniprot.org/uniprot/SHAN3_MOUSE SHAN3_MOUSE]] Major scaffold postsynaptic density protein which interacts with multiple proteins and complexes to orchestrate the dendritic spine and synapse formation, maturation and maintenance. Interconnects receptors of the postsynaptic membrane including NMDA-type and metabotropic glutamate receptors via complexes with GKAP/PSD-95 and HOMER, respectively, and the actin-based cytoskeleton. Plays a role in the structural and functional organization of the dendritic spine and synaptic junction through the interaction with Arp2/3 and WAVE1 complex as well as the promotion of the F-actin clusters. By way of this control of actin dynamics, participates in the regulation of developing neurons growth cone motility and the NMDA receptor-signaling. Also modulates GRIA1 exocytosis and GRM5/MGLUR5 expression and signaling to control the AMPA and metabotropic glutamate receptor-mediated synaptic transmission and plasticity. May be required at an early stage of synapse formation and be inhibited by IGF1 to promote synapse maturation.<ref>PMID:21423165</ref> <ref>PMID:21558424</ref> <ref>PMID:23739967</ref> <ref>PMID:24153177</ref>
+[[https://www.uniprot.org/uniprot/SHAN3_MOUSE SHAN3_MOUSE]] Major scaffold postsynaptic density protein which interacts with multiple proteins and complexes to orchestrate the dendritic spine and synapse formation, maturation and maintenance. Interconnects receptors of the postsynaptic membrane including NMDA-type and metabotropic glutamate receptors via complexes with GKAP/PSD-95 and HOMER, respectively, and the actin-based cytoskeleton. Plays a role in the structural and functional organization of the dendritic spine and synaptic junction through the interaction with Arp2/3 and WAVE1 complex as well as the promotion of the F-actin clusters. By way of this control of actin dynamics, participates in the regulation of developing neurons growth cone motility and the NMDA receptor-signaling. Also modulates GRIA1 exocytosis and GRM5/MGLUR5 expression and signaling to control the AMPA and metabotropic glutamate receptor-mediated synaptic transmission and plasticity. May be required at an early stage of synapse formation and be inhibited by IGF1 to promote synapse maturation.<ref>PMID:21423165</ref> <ref>PMID:21558424</ref> <ref>PMID:23739967</ref> <ref>PMID:24153177</ref>
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==
@@ Line 26: / Line 26: @@
 __TOC__
 </StructureSection>
+[[Category: Large Structures]]
 [[Category: Lk3 transgenic mice]]
 [[Category: Diehl, A]]

3o5n

From Proteopedia

Revision as of 07:16, 12 May 2022

Tetrahydroquinoline carboxylates are potent inhibitors of the Shank PDZ domain, a putative target in autism disorders

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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