7oaj

From Proteopedia

(Difference between revisions)

Current revision

Crystal structure of pseudokinase CASK in complex with compound 7

Structural highlights

7oaj is a 4 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 1.93Å
Ligands:	,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

CSKP_HUMAN Defects in CASK are the cause of mental retardation and microcephaly with pontine and cerebellar hypoplasia (MICPCH) [MIM:300749. A disorder characterized by significantly below average general intellectual functioning associated with impairments in adaptative behavior and manifested during the developmental period. Patients with mental retardation X-linked CASK-related can manifest a severe phenotype consisting of severe intellectual deficit, congenital or postnatal microcephaly, disproportionate brainstem and cerebellar hypoplasia. A milder phenotype consists of mental retardation alone or associated with nystagmus.^[1] Defects in CASK are the cause of FG syndrome type 4 (FGS4) [MIM:300422. FG syndrome (FGS) is an X-linked disorder characterized by mental retardation, relative macrocephaly, hypotonia and constipation.^[2]

Function

CSKP_HUMAN Multidomain scaffolding protein with a role in synaptic transmembrane protein anchoring and ion channel trafficking. Contributes to neural development and regulation of gene expression via interaction with the transcription factor TRB1. Binds to cell-surface proteins, including amyloid precursor protein, neurexins and syndecans. May mediate a link between the extracellular matrix and the actin cytoskeleton via its interaction with syndecan and with the actin/spectrin-binding protein 4.1.

Publication Abstract from PubMed

CASK (Ca(2+)/calmodulin-dependent Ser/Thr kinase) is a member of the MAGUK (membrane-associated guanylate kinase) family that functions as neurexin kinases with roles implicated in neuronal synapses and trafficking. The lack of a canonical DFG motif, which is altered to GFG in CASK, led to the classification as a pseudokinase. However, functional studies revealed that CASK can still phosphorylate substrates in the absence of divalent metals. CASK dysfunction has been linked to many diseases, including colorectal cancer, Parkinson's disease, and X-linked mental retardation, suggesting CASK as a potential drug target. Here, we exploited structure-based design for the development of highly potent and selective CASK inhibitors based on 2,4-diaminopyrimidine-5-carboxamides targeting an unusual pocket created by the GFG motif. The presented inhibitor design offers a more general strategy for the development of pseudokinase ligands that harbor unusual sequence motifs. It also provides a first chemical probe for studying the biological roles of CASK.

Design and Development of a Chemical Probe for Pseudokinase Ca(2+)/calmodulin-Dependent Ser/Thr Kinase.,Russ N, Schroder M, Berger BT, Mandel S, Aydogan Y, Mauer S, Pohl C, Drewry DH, Chaikuad A, Muller S, Knapp S J Med Chem. 2021 Oct 14;64(19):14358-14376. doi: 10.1021/acs.jmedchem.1c00845., Epub 2021 Sep 20. PMID:34543009^[3]

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

References

↑ Najm J, Horn D, Wimplinger I, Golden JA, Chizhikov VV, Sudi J, Christian SL, Ullmann R, Kuechler A, Haas CA, Flubacher A, Charnas LR, Uyanik G, Frank U, Klopocki E, Dobyns WB, Kutsche K. Mutations of CASK cause an X-linked brain malformation phenotype with microcephaly and hypoplasia of the brainstem and cerebellum. Nat Genet. 2008 Sep;40(9):1065-7. doi: 10.1038/ng.194. PMID:19165920 doi:10.1038/ng.194
↑ Piluso G, D'Amico F, Saccone V, Bismuto E, Rotundo IL, Di Domenico M, Aurino S, Schwartz CE, Neri G, Nigro V. A missense mutation in CASK causes FG syndrome in an Italian family. Am J Hum Genet. 2009 Feb;84(2):162-77. doi: 10.1016/j.ajhg.2008.12.018. Epub 2009, Feb 5. PMID:19200522 doi:10.1016/j.ajhg.2008.12.018
↑ Russ N, Schroder M, Berger BT, Mandel S, Aydogan Y, Mauer S, Pohl C, Drewry DH, Chaikuad A, Muller S, Knapp S. Design and Development of a Chemical Probe for Pseudokinase Ca(2+)/calmodulin-Dependent Ser/Thr Kinase. J Med Chem. 2021 Oct 14;64(19):14358-14376. doi: 10.1021/acs.jmedchem.1c00845., Epub 2021 Sep 20. PMID:34543009 doi:http://dx.doi.org/10.1021/acs.jmedchem.1c00845

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

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/7oaj"

Categories: Homo sapiens | Large Structures | Chaikuad A | Knapp S | Russ N

@@ Line 3: / Line 3: @@
 <StructureSection load='7oaj' size='340' side='right'caption='[[7oaj]], [[Resolution|resolution]] 1.93&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[7oaj]] is a 4 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=7OAJ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7OAJ FirstGlance]. <br>
+<table><tr><td colspan='2'>[[7oaj]] is a 4 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=7OAJ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7OAJ FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=V6E:4-(cyclopentylamino)-2-[(3,4-dichlorophenyl)methylamino]-N-[3-(2-oxidanylidenepyrrolidin-1-yl)propyl]pyrimidine-5-carboxamide'>V6E</scene></td></tr>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.93&#8491;</td></tr>
-<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">CASK, LIN2 ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=V6E:4-(cyclopentylamino)-2-[(3,4-dichlorophenyl)methylamino]-N-[3-(2-oxidanylidenepyrrolidin-1-yl)propyl]pyrimidine-5-carboxamide'>V6E</scene></td></tr>
-<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/Non-specific_serine/threonine_protein_kinase Non-specific serine/threonine protein kinase], with EC number [https://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.1 2.7.11.1] </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=7oaj FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7oaj OCA], [https://pdbe.org/7oaj PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7oaj RCSB], [https://www.ebi.ac.uk/pdbsum/7oaj PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7oaj ProSAT]</span></td></tr>
 </table>
 == Disease ==
-[[https://www.uniprot.org/uniprot/CSKP_HUMAN CSKP_HUMAN]] Defects in CASK are the cause of mental retardation and microcephaly with pontine and cerebellar hypoplasia (MICPCH) [MIM:[https://omim.org/entry/300749 300749]]. A disorder characterized by significantly below average general intellectual functioning associated with impairments in adaptative behavior and manifested during the developmental period. Patients with mental retardation X-linked CASK-related can manifest a severe phenotype consisting of severe intellectual deficit, congenital or postnatal microcephaly, disproportionate brainstem and cerebellar hypoplasia. A milder phenotype consists of mental retardation alone or associated with nystagmus.<ref>PMID:19165920</ref>   Defects in CASK are the cause of FG syndrome type 4 (FGS4) [MIM:[https://omim.org/entry/300422 300422]]. FG syndrome (FGS) is an X-linked disorder characterized by mental retardation, relative macrocephaly, hypotonia and constipation.<ref>PMID:19200522</ref>
+[https://www.uniprot.org/uniprot/CSKP_HUMAN CSKP_HUMAN] Defects in CASK are the cause of mental retardation and microcephaly with pontine and cerebellar hypoplasia (MICPCH) [MIM:[https://omim.org/entry/300749 300749]. A disorder characterized by significantly below average general intellectual functioning associated with impairments in adaptative behavior and manifested during the developmental period. Patients with mental retardation X-linked CASK-related can manifest a severe phenotype consisting of severe intellectual deficit, congenital or postnatal microcephaly, disproportionate brainstem and cerebellar hypoplasia. A milder phenotype consists of mental retardation alone or associated with nystagmus.<ref>PMID:19165920</ref>   Defects in CASK are the cause of FG syndrome type 4 (FGS4) [MIM:[https://omim.org/entry/300422 300422]. FG syndrome (FGS) is an X-linked disorder characterized by mental retardation, relative macrocephaly, hypotonia and constipation.<ref>PMID:19200522</ref>
 == Function ==
-[[https://www.uniprot.org/uniprot/CSKP_HUMAN CSKP_HUMAN]] Multidomain scaffolding protein with a role in synaptic transmembrane protein anchoring and ion channel trafficking. Contributes to neural development and regulation of gene expression via interaction with the transcription factor TRB1. Binds to cell-surface proteins, including amyloid precursor protein, neurexins and syndecans. May mediate a link between the extracellular matrix and the actin cytoskeleton via its interaction with syndecan and with the actin/spectrin-binding protein 4.1.
+[https://www.uniprot.org/uniprot/CSKP_HUMAN CSKP_HUMAN] Multidomain scaffolding protein with a role in synaptic transmembrane protein anchoring and ion channel trafficking. Contributes to neural development and regulation of gene expression via interaction with the transcription factor TRB1. Binds to cell-surface proteins, including amyloid precursor protein, neurexins and syndecans. May mediate a link between the extracellular matrix and the actin cytoskeleton via its interaction with syndecan and with the actin/spectrin-binding protein 4.1.
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==
@@ Line 26: / Line 25: @@
 __TOC__
 </StructureSection>
-[[Category: Human]]
+[[Category: Homo sapiens]]
 [[Category: Large Structures]]
-[[Category: Non-specific serine/threonine protein kinase]]
+[[Category: Chaikuad A]]
-[[Category: Chaikuad, A]]
+[[Category: Knapp S]]
-[[Category: Knapp, S]]
+[[Category: Russ N]]
-[[Category: Russ, N]]
-[[Category: Structural genomic]]
-[[Category: Inhibitor]]
-[[Category: Kinase]]
-[[Category: Pseudokinase]]
-[[Category: Sgc]]
-[[Category: Transferase]]

7oaj

From Proteopedia

Current revision

Crystal structure of pseudokinase CASK in complex with compound 7

Structural highlights

Disease

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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