5t8p: Difference between revisions

Latest revision as of 12:19, 9 May 2024

Crystal structure of murine NF-kappaB inducing kinase (NIK) bound to benzoxepin compound 2

Structural highlights

5t8p is a 2 chain structure with sequence from Mus musculus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.32Å
Ligands:	774, SO4
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 benzoxepin compound 2==
-<StructureSection load='5t8p' size='340' side='right' caption='[[5t8p]], [[Resolution|resolution]] 2.32&Aring;' scene=''>
+<StructureSection load='5t8p' size='340' side='right'caption='[[5t8p]], [[Resolution|resolution]] 2.32&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[5t8p]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5T8P OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5T8P FirstGlance]. <br>
+<table><tr><td colspan='2'>[[5t8p]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Mus_musculus Mus musculus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5T8P OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5T8P FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=774:6,7-DIHYDROTHIENO[4,5]OXEPINO[1,2-~{C}]PYRIDINE-2-CARBOXAMIDE'>774</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</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]] 2.32&#8491;</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='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=774:6,7-DIHYDROTHIENO[4,5]OXEPINO[1,2-~{C}]PYRIDINE-2-CARBOXAMIDE'>774</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></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=5t8p FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5t8p OCA], [http://pdbe.org/5t8p PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5t8p RCSB], [http://www.ebi.ac.uk/pdbsum/5t8p PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5t8p 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=5t8p FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5t8p OCA], [https://pdbe.org/5t8p PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5t8p RCSB], [https://www.ebi.ac.uk/pdbsum/5t8p PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5t8p ProSAT]</span></td></tr>
 </table>
 == Function ==
-[[http://www.uniprot.org/uniprot/M3K14_MOUSE 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.<ref>PMID:11239468</ref>
+[https://www.uniprot.org/uniprot/M3K14_MOUSE 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.<ref>PMID:11239468</ref>
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==
@@ Line 23: / Line 23: @@
 __TOC__
 </StructureSection>
-[[Category: Mitogen-activated protein kinase kinase kinase]]
+[[Category: Large Structures]]
-[[Category: McEwan, P A]]
+[[Category: Mus musculus]]
-[[Category: Smith, M A]]
+[[Category: McEwan PA]]
-[[Category: Map3k14]]
+[[Category: Smith MA]]
-[[Category: Nf-kappab]]
-[[Category: Protein serine/threonine kinase]]
-[[Category: Transferase]]

5t8p: Difference between revisions

Latest revision as of 12:19, 9 May 2024

Crystal structure of murine NF-kappaB inducing kinase (NIK) bound to benzoxepin compound 2

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

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