5t8q: Difference between revisions

Revision as of 11:26, 16 September 2020

Crystal structure of murine NF-kappaB inducing kinase (NIK) bound to aryl pyrrole fragment 17

Structural highlights

5t8q is a 2 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:	76Y, SO4
Gene:	Map3k14, Nik (LK3 transgenic mice)
Activity:	Mitogen-activated protein kinase kinase kinase, with EC number 2.7.11.25
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

[M3K14_MOUSE] Lymphotoxin beta-activated kinase which seems to be exclusively involved in the activation of NF-kappa-B and its transcriptional activity. Promotes proteolytic processing of NFKB2/P100, which leads to activation of NF-kappa-B via the non-canonical pathway. Could act in a receptor-selective manner.^[1]

Publication Abstract from PubMed

We report here structure-guided optimization of a novel series of NF-kappaB inducing kinase (NIK) inhibitors. Starting from a modestly potent, low molecular weight lead, activity was improved by designing a type 11/2 binding mode that accessed a back pocket past the methionine-471 gatekeeper. Divergent binding modes in NIK and PI3K were exploited to dampen PI3K inhibition while maintaining NIK inhibition within these series. Potent compounds were discovered that selectively inhibit the nuclear translocation of NF-kappaB2 (p52/REL-B) but not canonical NF-kappaB1 (REL-A/p50).

Structure-Based Design of Tricyclic NF-kappaB Inducing Kinase (NIK) Inhibitors That Have High Selectivity over Phosphoinositide-3-kinase (PI3K).,Castanedo GM, Blaquiere N, Beresini M, Bravo B, Brightbill H, Chen J, Cui HF, Eigenbrot C, Everett C, Feng J, Godemann R, Gogol E, Hymowitz S, Johnson A, Kayagaki N, Kohli PB, Knuppel K, Kraemer J, Kruger S, Loke P, McEwan P, Montalbetti C, Roberts DA, Smith M, Steinbacher S, Sujatha-Bhaskar S, Takahashi R, Wang X, Wu LC, Zhang Y, Staben ST J Med Chem. 2017 Jan 12. doi: 10.1021/acs.jmedchem.6b01363. PMID:28005357^[2]

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

References

↑ Xiao G, Harhaj EW, Sun SC. NF-kappaB-inducing kinase regulates the processing of NF-kappaB2 p100. Mol Cell. 2001 Feb;7(2):401-9. PMID:11239468
↑ Castanedo GM, Blaquiere N, Beresini M, Bravo B, Brightbill H, Chen J, Cui HF, Eigenbrot C, Everett C, Feng J, Godemann R, Gogol E, Hymowitz S, Johnson A, Kayagaki N, Kohli PB, Knuppel K, Kraemer J, Kruger S, Loke P, McEwan P, Montalbetti C, Roberts DA, Smith M, Steinbacher S, Sujatha-Bhaskar S, Takahashi R, Wang X, Wu LC, Zhang Y, Staben ST. Structure-Based Design of Tricyclic NF-kappaB Inducing Kinase (NIK) Inhibitors That Have High Selectivity over Phosphoinositide-3-kinase (PI3K). J Med Chem. 2017 Jan 12. doi: 10.1021/acs.jmedchem.6b01363. PMID:28005357 doi:https://dx.doi.org/10.1021/acs.jmedchem.6b01363

Proteopedia Page Contributors and Editors (what is this?)

OCA

[1] Xiao G, Harhaj EW, Sun SC. NF-kappaB-inducing kinase regulates the processing of NF-kappaB2 p100. Mol Cell. 2001 Feb;7(2):401-9. PMID:11239468

[2] Castanedo GM, Blaquiere N, Beresini M, Bravo B, Brightbill H, Chen J, Cui HF, Eigenbrot C, Everett C, Feng J, Godemann R, Gogol E, Hymowitz S, Johnson A, Kayagaki N, Kohli PB, Knuppel K, Kraemer J, Kruger S, Loke P, McEwan P, Montalbetti C, Roberts DA, Smith M, Steinbacher S, Sujatha-Bhaskar S, Takahashi R, Wang X, Wu LC, Zhang Y, Staben ST. Structure-Based Design of Tricyclic NF-kappaB Inducing Kinase (NIK) Inhibitors That Have High Selectivity over Phosphoinositide-3-kinase (PI3K). J Med Chem. 2017 Jan 12. doi: 10.1021/acs.jmedchem.6b01363. PMID:28005357 doi:https://dx.doi.org/10.1021/acs.jmedchem.6b01363

[1]

[2]

@@ Line 1: / Line 1: @@
 ==Crystal structure of murine NF-kappaB inducing kinase (NIK) bound to aryl pyrrole fragment 17==
-<StructureSection load='5t8q' size='340' side='right' caption='[[5t8q]], [[Resolution|resolution]] 2.63&Aring;' scene=''>
+<StructureSection load='5t8q' size='340' side='right'caption='[[5t8q]], [[Resolution|resolution]] 2.63&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[5t8q]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5T8Q OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5T8Q FirstGlance]. <br>
+<table><tr><td colspan='2'>[[5t8q]] is a 2 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=5T8Q OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=5T8Q FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=76Y:1-[(2-CHLOROPHENYL)METHYL]PYRROLE-2-CARBOXAMIDE'>76Y</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
+</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=76Y:1-[(2-CHLOROPHENYL)METHYL]PYRROLE-2-CARBOXAMIDE'>76Y</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
+<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">Map3k14, Nik ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=10090 LK3 transgenic mice])</td></tr>
 <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Mitogen-activated_protein_kinase_kinase_kinase Mitogen-activated protein kinase kinase kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.25 2.7.11.25] </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=5t8q FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5t8q OCA], [http://pdbe.org/5t8q PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5t8q RCSB], [http://www.ebi.ac.uk/pdbsum/5t8q PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5t8q ProSAT]</span></td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=5t8q FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5t8q OCA], [http://pdbe.org/5t8q PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5t8q RCSB], [http://www.ebi.ac.uk/pdbsum/5t8q PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5t8q ProSAT]</span></td></tr>
 </table>
 == Function ==
@@ Line 23: / Line 24: @@
 __TOC__
 </StructureSection>
+[[Category: Large Structures]]
+[[Category: Lk3 transgenic mice]]
 [[Category: Mitogen-activated protein kinase kinase kinase]]
 [[Category: Hymowitz, S G]]

5t8q: Difference between revisions

Revision as of 11:26, 16 September 2020

Crystal structure of murine NF-kappaB inducing kinase (NIK) bound to aryl pyrrole fragment 17

Structural highlights

Function

Publication Abstract from PubMed

References

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