6jlr: Difference between revisions

Latest revision as of 10:15, 22 November 2023

Crystal structure of wild type MNK2 in complex with inhibitor

Structural highlights

6jlr is a 1 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 2.901Å
Ligands:	BV9
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

MKNK2_HUMAN Serine/threonine-protein kinase that phosphorylates SFPQ/PSF, HNRNPA1 and EIF4E. May play a role in the response to environmental stress and cytokines. Appears to regulate translation by phosphorylating EIF4E, thus increasing the affinity of this protein for the 7-methylguanosine-containing mRNA cap. Required for mediating PP2A-inhibition-induced EIF4E phosphorylation. Triggers EIF4E shuttling from cytoplasm to nucleus. Isoform 1 displays a high basal kinase activity, but isoform 2 exhibits a very low kinase activity. Acts as a mediator of the suppressive effects of IFNgamma on hematopoiesis. Negative regulator for signals that control generation of arsenic trioxide As(2)O(3)-dependent apoptosis and anti-leukemic responses. Involved in anti-apoptotic signaling in response to serum withdrawal.^[1] ^[2] ^[3] ^[4] ^[5] ^[6] ^[7] ^[8] ^[9]

Publication Abstract from PubMed

Dysregulation of translation initiation factor 4E (eIF4E) activity occurs in various cancers. Mitogen-activated protein kinase (MAPK) interacting kinases 1 and 2 (MNK1 and MNK2) play a fundamental role in activation of eIF4E. Structure-activity relationship-driven expansion of a fragment hit led to discovery of dual MNK1 and MNK2 inhibitors based on a novel pyridine-benzamide scaffold. The compounds possess promising in vitro and in vivo pharmacokinetic profiles and show potent on target inhibition of eIF4E phosphorylation in cells.

Stepwise Evolution of Fragment Hits against MAPK Interacting Kinases 1 and 2.,Kwiatkowski J, Liu B, Pang S, Ahmad NHB, Wang G, Poulsen A, Yang H, Poh YR, Tee DHY, Ong E, Retna P, Dinie N, Kwek P, Wee JLK, Manoharan V, Low CB, Seah PG, Pendharkar V, Sangthongpitag K, Joy J, Baburajendran N, Jansson AE, Nacro K, Hill J, Keller TH, Hung AW J Med Chem. 2020 Jan 23;63(2):621-637. doi: 10.1021/acs.jmedchem.9b01582. Epub, 2020 Jan 7. PMID:31910010^[10]

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

References

↑ Scheper GC, Morrice NA, Kleijn M, Proud CG. The mitogen-activated protein kinase signal-integrating kinase Mnk2 is a eukaryotic initiation factor 4E kinase with high levels of basal activity in mammalian cells. Mol Cell Biol. 2001 Feb;21(3):743-54. PMID:11154262 doi:10.1128/MCB.21.3.743-754.2001
↑ Knauf U, Tschopp C, Gram H. Negative regulation of protein translation by mitogen-activated protein kinase-interacting kinases 1 and 2. Mol Cell Biol. 2001 Aug;21(16):5500-11. PMID:11463832 doi:https://dx.doi.org/10.1128/MCB.21.16.5500-5511.2001
↑ Scheper GC, Parra JL, Wilson M, Van Kollenburg B, Vertegaal AC, Han ZG, Proud CG. The N and C termini of the splice variants of the human mitogen-activated protein kinase-interacting kinase Mnk2 determine activity and localization. Mol Cell Biol. 2003 Aug;23(16):5692-705. PMID:12897141
↑ Buxade M, Parra JL, Rousseau S, Shpiro N, Marquez R, Morrice N, Bain J, Espel E, Proud CG. The Mnks are novel components in the control of TNF alpha biosynthesis and phosphorylate and regulate hnRNP A1. Immunity. 2005 Aug;23(2):177-89. PMID:16111636 doi:https://dx.doi.org/10.1016/j.immuni.2005.06.009
↑ Buxade M, Morrice N, Krebs DL, Proud CG. The PSF.p54nrb complex is a novel Mnk substrate that binds the mRNA for tumor necrosis factor alpha. J Biol Chem. 2008 Jan 4;283(1):57-65. Epub 2007 Oct 26. PMID:17965020 doi:https://dx.doi.org/10.1074/jbc.M705286200
↑ Dolniak B, Katsoulidis E, Carayol N, Altman JK, Redig AJ, Tallman MS, Ueda T, Watanabe-Fukunaga R, Fukunaga R, Platanias LC. Regulation of arsenic trioxide-induced cellular responses by Mnk1 and Mnk2. J Biol Chem. 2008 May 2;283(18):12034-42. doi: 10.1074/jbc.M708816200. Epub 2008 , Feb 25. PMID:18299328 doi:https://dx.doi.org/10.1074/jbc.M708816200
↑ Shveygert M, Kaiser C, Bradrick SS, Gromeier M. Regulation of eukaryotic initiation factor 4E (eIF4E) phosphorylation by mitogen-activated protein kinase occurs through modulation of Mnk1-eIF4G interaction. Mol Cell Biol. 2010 Nov;30(21):5160-7. doi: 10.1128/MCB.00448-10. Epub 2010 Sep, 7. PMID:20823271 doi:https://dx.doi.org/10.1128/MCB.00448-10
↑ Li Y, Yue P, Deng X, Ueda T, Fukunaga R, Khuri FR, Sun SY. Protein phosphatase 2A negatively regulates eukaryotic initiation factor 4E phosphorylation and eIF4F assembly through direct dephosphorylation of Mnk and eIF4E. Neoplasia. 2010 Oct;12(10):848-55. PMID:20927323
↑ Joshi S, Sharma B, Kaur S, Majchrzak B, Ueda T, Fukunaga R, Verma AK, Fish EN, Platanias LC. Essential role for Mnk kinases in type II interferon (IFNgamma) signaling and its suppressive effects on normal hematopoiesis. J Biol Chem. 2011 Feb 25;286(8):6017-26. doi: 10.1074/jbc.M110.197921. Epub 2010 , Dec 13. PMID:21149447 doi:https://dx.doi.org/10.1074/jbc.M110.197921
↑ Kwiatkowski J, Liu B, Pang S, Ahmad NHB, Wang G, Poulsen A, Yang H, Poh YR, Tee DHY, Ong E, Retna P, Dinie N, Kwek P, Wee JLK, Manoharan V, Low CB, Seah PG, Pendharkar V, Sangthongpitag K, Joy J, Baburajendran N, Jansson AE, Nacro K, Hill J, Keller TH, Hung AW. Stepwise Evolution of Fragment Hits against MAPK Interacting Kinases 1 and 2. J Med Chem. 2020 Jan 23;63(2):621-637. doi: 10.1021/acs.jmedchem.9b01582. Epub, 2020 Jan 7. PMID:31910010 doi:https://dx.doi.org/10.1021/acs.jmedchem.9b01582

Proteopedia Page Contributors and Editors (what is this?)

OCA

[1] Scheper GC, Morrice NA, Kleijn M, Proud CG. The mitogen-activated protein kinase signal-integrating kinase Mnk2 is a eukaryotic initiation factor 4E kinase with high levels of basal activity in mammalian cells. Mol Cell Biol. 2001 Feb;21(3):743-54. PMID:11154262 doi:10.1128/MCB.21.3.743-754.2001

[2] Knauf U, Tschopp C, Gram H. Negative regulation of protein translation by mitogen-activated protein kinase-interacting kinases 1 and 2. Mol Cell Biol. 2001 Aug;21(16):5500-11. PMID:11463832 doi:https://dx.doi.org/10.1128/MCB.21.16.5500-5511.2001

[3] Scheper GC, Parra JL, Wilson M, Van Kollenburg B, Vertegaal AC, Han ZG, Proud CG. The N and C termini of the splice variants of the human mitogen-activated protein kinase-interacting kinase Mnk2 determine activity and localization. Mol Cell Biol. 2003 Aug;23(16):5692-705. PMID:12897141

[4] Buxade M, Parra JL, Rousseau S, Shpiro N, Marquez R, Morrice N, Bain J, Espel E, Proud CG. The Mnks are novel components in the control of TNF alpha biosynthesis and phosphorylate and regulate hnRNP A1. Immunity. 2005 Aug;23(2):177-89. PMID:16111636 doi:https://dx.doi.org/10.1016/j.immuni.2005.06.009

[5] Buxade M, Morrice N, Krebs DL, Proud CG. The PSF.p54nrb complex is a novel Mnk substrate that binds the mRNA for tumor necrosis factor alpha. J Biol Chem. 2008 Jan 4;283(1):57-65. Epub 2007 Oct 26. PMID:17965020 doi:https://dx.doi.org/10.1074/jbc.M705286200

[6] Dolniak B, Katsoulidis E, Carayol N, Altman JK, Redig AJ, Tallman MS, Ueda T, Watanabe-Fukunaga R, Fukunaga R, Platanias LC. Regulation of arsenic trioxide-induced cellular responses by Mnk1 and Mnk2. J Biol Chem. 2008 May 2;283(18):12034-42. doi: 10.1074/jbc.M708816200. Epub 2008 , Feb 25. PMID:18299328 doi:https://dx.doi.org/10.1074/jbc.M708816200

[7] Shveygert M, Kaiser C, Bradrick SS, Gromeier M. Regulation of eukaryotic initiation factor 4E (eIF4E) phosphorylation by mitogen-activated protein kinase occurs through modulation of Mnk1-eIF4G interaction. Mol Cell Biol. 2010 Nov;30(21):5160-7. doi: 10.1128/MCB.00448-10. Epub 2010 Sep, 7. PMID:20823271 doi:https://dx.doi.org/10.1128/MCB.00448-10

[8] Li Y, Yue P, Deng X, Ueda T, Fukunaga R, Khuri FR, Sun SY. Protein phosphatase 2A negatively regulates eukaryotic initiation factor 4E phosphorylation and eIF4F assembly through direct dephosphorylation of Mnk and eIF4E. Neoplasia. 2010 Oct;12(10):848-55. PMID:20927323

[9] Joshi S, Sharma B, Kaur S, Majchrzak B, Ueda T, Fukunaga R, Verma AK, Fish EN, Platanias LC. Essential role for Mnk kinases in type II interferon (IFNgamma) signaling and its suppressive effects on normal hematopoiesis. J Biol Chem. 2011 Feb 25;286(8):6017-26. doi: 10.1074/jbc.M110.197921. Epub 2010 , Dec 13. PMID:21149447 doi:https://dx.doi.org/10.1074/jbc.M110.197921

[10] Kwiatkowski J, Liu B, Pang S, Ahmad NHB, Wang G, Poulsen A, Yang H, Poh YR, Tee DHY, Ong E, Retna P, Dinie N, Kwek P, Wee JLK, Manoharan V, Low CB, Seah PG, Pendharkar V, Sangthongpitag K, Joy J, Baburajendran N, Jansson AE, Nacro K, Hill J, Keller TH, Hung AW. Stepwise Evolution of Fragment Hits against MAPK Interacting Kinases 1 and 2. J Med Chem. 2020 Jan 23;63(2):621-637. doi: 10.1021/acs.jmedchem.9b01582. Epub, 2020 Jan 7. PMID:31910010 doi:https://dx.doi.org/10.1021/acs.jmedchem.9b01582

[1]

[2]

[3]

[4]

[5]

[6]

[7]

[8]

[9]

[10]

@@ Line 3: / Line 3: @@
 <StructureSection load='6jlr' size='340' side='right'caption='[[6jlr]], [[Resolution|resolution]] 2.90&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[6jlr]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6JLR OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6JLR FirstGlance]. <br>
+<table><tr><td colspan='2'>[[6jlr]] is a 1 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=6JLR OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6JLR FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=BV9:4-[5-(1-methylpyrazol-4-yl)pyridin-3-yl]benzamide'>BV9</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]] 2.901&#8491;</td></tr>
-<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Non-specific_serine/threonine_protein_kinase Non-specific serine/threonine protein kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.1 2.7.11.1] </span></td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=BV9:4-[5-(1-methylpyrazol-4-yl)pyridin-3-yl]benzamide'>BV9</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=6jlr FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6jlr OCA], [http://pdbe.org/6jlr PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6jlr RCSB], [http://www.ebi.ac.uk/pdbsum/6jlr PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6jlr 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=6jlr FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6jlr OCA], [https://pdbe.org/6jlr PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6jlr RCSB], [https://www.ebi.ac.uk/pdbsum/6jlr PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6jlr ProSAT]</span></td></tr>
 </table>
 == Function ==
-[[http://www.uniprot.org/uniprot/MKNK2_HUMAN MKNK2_HUMAN]] Serine/threonine-protein kinase that phosphorylates SFPQ/PSF, HNRNPA1 and EIF4E. May play a role in the response to environmental stress and cytokines. Appears to regulate translation by phosphorylating EIF4E, thus increasing the affinity of this protein for the 7-methylguanosine-containing mRNA cap. Required for mediating PP2A-inhibition-induced EIF4E phosphorylation. Triggers EIF4E shuttling from cytoplasm to nucleus. Isoform 1 displays a high basal kinase activity, but isoform 2 exhibits a very low kinase activity. Acts as a mediator of the suppressive effects of IFNgamma on hematopoiesis. Negative regulator for signals that control generation of arsenic trioxide As(2)O(3)-dependent apoptosis and anti-leukemic responses. Involved in anti-apoptotic signaling in response to serum withdrawal.<ref>PMID:11154262</ref> <ref>PMID:11463832</ref> <ref>PMID:12897141</ref> <ref>PMID:16111636</ref> <ref>PMID:17965020</ref> <ref>PMID:18299328</ref> <ref>PMID:20823271</ref> <ref>PMID:20927323</ref> <ref>PMID:21149447</ref>
+[https://www.uniprot.org/uniprot/MKNK2_HUMAN MKNK2_HUMAN] Serine/threonine-protein kinase that phosphorylates SFPQ/PSF, HNRNPA1 and EIF4E. May play a role in the response to environmental stress and cytokines. Appears to regulate translation by phosphorylating EIF4E, thus increasing the affinity of this protein for the 7-methylguanosine-containing mRNA cap. Required for mediating PP2A-inhibition-induced EIF4E phosphorylation. Triggers EIF4E shuttling from cytoplasm to nucleus. Isoform 1 displays a high basal kinase activity, but isoform 2 exhibits a very low kinase activity. Acts as a mediator of the suppressive effects of IFNgamma on hematopoiesis. Negative regulator for signals that control generation of arsenic trioxide As(2)O(3)-dependent apoptosis and anti-leukemic responses. Involved in anti-apoptotic signaling in response to serum withdrawal.<ref>PMID:11154262</ref> <ref>PMID:11463832</ref> <ref>PMID:12897141</ref> <ref>PMID:16111636</ref> <ref>PMID:17965020</ref> <ref>PMID:18299328</ref> <ref>PMID:20823271</ref> <ref>PMID:20927323</ref> <ref>PMID:21149447</ref>
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==
@@ Line 23: / Line 23: @@
 __TOC__
 </StructureSection>
+[[Category: Homo sapiens]]
 [[Category: Large Structures]]
-[[Category: Non-specific serine/threonine protein kinase]]
+[[Category: Baburajendran N]]
-[[Category: Baburajendran, N]]
+[[Category: Hill J]]
-[[Category: Hill, J]]
-[[Category: Cancer]]
-[[Category: Inhibitor]]
-[[Category: Kinase]]
-[[Category: Kinase domain]]
-[[Category: Mnk]]
-[[Category: Phosphorylation]]
-[[Category: Transferase]]
-[[Category: Transferase-transferase inhibitor complex]]

6jlr: Difference between revisions

Latest revision as of 10:15, 22 November 2023

Crystal structure of wild type MNK2 in complex with inhibitor

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Navigation menu

Page actions

Page actions

Personal tools

Navigation

Search

Tools