8afr

From Proteopedia

(Difference between revisions)

Revision as of 11:19, 1 February 2023

Pim1 in complex with 4-((6-hydroxybenzofuran-3-yl)methyl)benzoic acid and Pimtide

Structural highlights

8afr is a 2 chain structure with sequence from Homo sapiens and Synthetic construct. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

PIM1_HUMAN Proto-oncogene with serine/threonine kinase activity involved in cell survival and cell proliferation and thus providing a selective advantage in tumorigenesis. Exerts its oncogenic activity through: the regulation of MYC transcriptional activity, the regulation of cell cycle progression and by phosphorylation and inhibition of proapoptotic proteins (BAD, MAP3K5, FOXO3). Phosphorylation of MYC leads to an increase of MYC protein stability and thereby an increase of transcriptional activity. The stabilization of MYC exerted by PIM1 might explain partly the strong synergism between these two oncogenes in tumorigenesis. Mediates survival signaling through phosphorylation of BAD, which induces release of the anti-apoptotic protein Bcl-X(L)/BCL2L1. Phosphorylation of MAP3K5, an other proapoptotic protein, by PIM1, significantly decreases MAP3K5 kinase activity and inhibits MAP3K5-mediated phosphorylation of JNK and JNK/p38MAPK subsequently reducing caspase-3 activation and cell apoptosis. Stimulates cell cycle progression at the G1-S and G2-M transitions by phosphorylation of CDC25A and CDC25C. Phosphorylation of CDKN1A, a regulator of cell cycle progression at G1, results in the relocation of CDKN1A to the cytoplasm and enhanced CDKN1A protein stability. Promote cell cycle progression and tumorigenesis by down-regulating expression of a regulator of cell cycle progression, CDKN1B, at both transcriptional and post-translational levels. Phosphorylation of CDKN1B,induces 14-3-3-proteins binding, nuclear export and proteasome-dependent degradation. May affect the structure or silencing of chromatin by phosphorylating HP1 gamma/CBX3. Acts also as a regulator of homing and migration of bone marrow cells involving functional interaction with the CXCL12-CXCR4 signaling axis.^[1] ^[2] ^[3] ^[4] ^[5] ^[6] ^[7]

Publication Abstract from PubMed

In this study, fragment-sized hits binding to Pim-1 kinase with initially modest affinity were further optimized by combining computational, synthetic and crystallographic expertise, eventually resulting in potent ligands with affinities in the nanomolar range that address rarely-targeted regions of Pim-1 kinase. Starting from a set of crystallographically validated, chemically distinct fragments that bind to Pim-1 kinase but lack typical nucleotide mimetic structures, a library of extended fragments was built by exhaustive in silico reactions. After docking, minimization, clustering, visual inspection of the top-ranked compounds, and evaluation of ease of synthetic accessibility, either the original compound or a close derivative was synthesized and tested against Pim-1. For compounds showing the highest degree of Pim-1 inhibition the binding mode was determined crystallographically. Following a structure-guided approach, these were further optimized in a subsequent design cycle improving the compound's initial affinity by several orders of magnitude while synthesizing only a comparatively modest number of derivatives. The combination of computational and experimental approaches resulted in the development of a reasonably potent, novel molecular scaffold for inhibition of Pim-1 that targets specific surface regions, such as the interaction with R122 and P123 of the hinge region, which has been less frequently investigated in similar studies.

Pose, duplicate, then elaborate: Steps towards increased affinity for inhibitors targeting the specificity surface of the Pim-1 kinase.,Heyder L, Hochban PMM, Taylor C, Chevillard F, Siefker C, Iking C, Borchardt H, Aigner A, Klebe G, Heine A, Kolb P, Diederich WE Eur J Med Chem. 2023 Jan 5;245(Pt 1):114914. doi: 10.1016/j.ejmech.2022.114914. , Epub 2022 Nov 9. PMID:36410167^[8]

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

References

↑ Saris CJ, Domen J, Berns A. The pim-1 oncogene encodes two related protein-serine/threonine kinases by alternative initiation at AUG and CUG. EMBO J. 1991 Mar;10(3):655-64. PMID:1825810
↑ Koike N, Maita H, Taira T, Ariga H, Iguchi-Ariga SM. Identification of heterochromatin protein 1 (HP1) as a phosphorylation target by Pim-1 kinase and the effect of phosphorylation on the transcriptional repression function of HP1(1). FEBS Lett. 2000 Feb 4;467(1):17-21. PMID:10664448
↑ Wang Z, Bhattacharya N, Mixter PF, Wei W, Sedivy J, Magnuson NS. Phosphorylation of the cell cycle inhibitor p21Cip1/WAF1 by Pim-1 kinase. Biochim Biophys Acta. 2002 Dec 16;1593(1):45-55. PMID:12431783
↑ Stout BA, Bates ME, Liu LY, Farrington NN, Bertics PJ. IL-5 and granulocyte-macrophage colony-stimulating factor activate STAT3 and STAT5 and promote Pim-1 and cyclin D3 protein expression in human eosinophils. J Immunol. 2004 Nov 15;173(10):6409-17. PMID:15528381
↑ Bachmann M, Kosan C, Xing PX, Montenarh M, Hoffmann I, Moroy T. The oncogenic serine/threonine kinase Pim-1 directly phosphorylates and activates the G2/M specific phosphatase Cdc25C. Int J Biochem Cell Biol. 2006 Mar;38(3):430-43. Epub 2005 Nov 8. PMID:16356754 doi:10.1016/j.biocel.2005.10.010
↑ Morishita D, Katayama R, Sekimizu K, Tsuruo T, Fujita N. Pim kinases promote cell cycle progression by phosphorylating and down-regulating p27Kip1 at the transcriptional and posttranscriptional levels. Cancer Res. 2008 Jul 1;68(13):5076-85. doi: 10.1158/0008-5472.CAN-08-0634. PMID:18593906 doi:10.1158/0008-5472.CAN-08-0634
↑ Gu JJ, Wang Z, Reeves R, Magnuson NS. PIM1 phosphorylates and negatively regulates ASK1-mediated apoptosis. Oncogene. 2009 Dec 3;28(48):4261-71. doi: 10.1038/onc.2009.276. Epub 2009 Sep 14. PMID:19749799 doi:10.1038/onc.2009.276
↑ Heyder L, Hochban PMM, Taylor C, Chevillard F, Siefker C, Iking C, Borchardt H, Aigner A, Klebe G, Heine A, Kolb P, Diederich WE. Pose, duplicate, then elaborate: Steps towards increased affinity for inhibitors targeting the specificity surface of the Pim-1 kinase. Eur J Med Chem. 2023 Jan 5;245(Pt 1):114914. doi: 10.1016/j.ejmech.2022.114914. , Epub 2022 Nov 9. PMID:36410167 doi:http://dx.doi.org/10.1016/j.ejmech.2022.114914

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

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/8afr"

@@ Line 1: / Line 1: @@
-'''Unreleased structure'''
-The entry 8afr is ON HOLD  until Paper Publication
+==Pim1 in complex with 4-((6-hydroxybenzofuran-3-yl)methyl)benzoic acid and Pimtide==
+<StructureSection load='8afr' size='340' side='right'caption='[[8afr]], [[Resolution|resolution]] 2.15&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[8afr]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [https://en.wikipedia.org/wiki/Synthetic_construct Synthetic construct]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=8AFR OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8AFR FirstGlance]. <br>
+</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=M0F:4-((6-hydroxybenzofuran-3-yl)methyl)benzoic+acid'>M0F</scene>, <scene name='pdbligand=SEP:PHOSPHOSERINE'>SEP</scene></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=8afr FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8afr OCA], [https://pdbe.org/8afr PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8afr RCSB], [https://www.ebi.ac.uk/pdbsum/8afr PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8afr ProSAT]</span></td></tr>
+</table>
+== Function ==
+[https://www.uniprot.org/uniprot/PIM1_HUMAN PIM1_HUMAN] Proto-oncogene with serine/threonine kinase activity involved in cell survival and cell proliferation and thus providing a selective advantage in tumorigenesis. Exerts its oncogenic activity through: the regulation of MYC transcriptional activity, the regulation of cell cycle progression and by phosphorylation and inhibition of proapoptotic proteins (BAD, MAP3K5, FOXO3). Phosphorylation of MYC leads to an increase of MYC protein stability and thereby an increase of transcriptional activity. The stabilization of MYC exerted by PIM1 might explain partly the strong synergism between these two oncogenes in tumorigenesis. Mediates survival signaling through phosphorylation of BAD, which induces release of the anti-apoptotic protein Bcl-X(L)/BCL2L1. Phosphorylation of MAP3K5, an other proapoptotic protein, by PIM1, significantly decreases MAP3K5 kinase activity and inhibits MAP3K5-mediated phosphorylation of JNK and JNK/p38MAPK subsequently reducing caspase-3 activation and cell apoptosis. Stimulates cell cycle progression at the G1-S and G2-M transitions by phosphorylation of CDC25A and CDC25C. Phosphorylation of CDKN1A, a regulator of cell cycle progression at G1, results in the relocation of CDKN1A to the cytoplasm and enhanced CDKN1A protein stability. Promote cell cycle progression and tumorigenesis by down-regulating expression of a regulator of cell cycle progression, CDKN1B, at both transcriptional and post-translational levels. Phosphorylation of CDKN1B,induces 14-3-3-proteins binding, nuclear export and proteasome-dependent degradation. May affect the structure or silencing of chromatin by phosphorylating HP1 gamma/CBX3. Acts also as a regulator of homing and migration of bone marrow cells involving functional interaction with the CXCL12-CXCR4 signaling axis.<ref>PMID:1825810</ref> <ref>PMID:10664448</ref> <ref>PMID:12431783</ref> <ref>PMID:15528381</ref> <ref>PMID:16356754</ref> <ref>PMID:18593906</ref> <ref>PMID:19749799</ref>
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+In this study, fragment-sized hits binding to Pim-1 kinase with initially modest affinity were further optimized by combining computational, synthetic and crystallographic expertise, eventually resulting in potent ligands with affinities in the nanomolar range that address rarely-targeted regions of Pim-1 kinase. Starting from a set of crystallographically validated, chemically distinct fragments that bind to Pim-1 kinase but lack typical nucleotide mimetic structures, a library of extended fragments was built by exhaustive in silico reactions. After docking, minimization, clustering, visual inspection of the top-ranked compounds, and evaluation of ease of synthetic accessibility, either the original compound or a close derivative was synthesized and tested against Pim-1. For compounds showing the highest degree of Pim-1 inhibition the binding mode was determined crystallographically. Following a structure-guided approach, these were further optimized in a subsequent design cycle improving the compound's initial affinity by several orders of magnitude while synthesizing only a comparatively modest number of derivatives. The combination of computational and experimental approaches resulted in the development of a reasonably potent, novel molecular scaffold for inhibition of Pim-1 that targets specific surface regions, such as the interaction with R122 and P123 of the hinge region, which has been less frequently investigated in similar studies.
-Authors: Hochban, P.M.M., Heine, A., Diederich, W.E.
+Pose, duplicate, then elaborate: Steps towards increased affinity for inhibitors targeting the specificity surface of the Pim-1 kinase.,Heyder L, Hochban PMM, Taylor C, Chevillard F, Siefker C, Iking C, Borchardt H, Aigner A, Klebe G, Heine A, Kolb P, Diederich WE Eur J Med Chem. 2023 Jan 5;245(Pt 1):114914. doi: 10.1016/j.ejmech.2022.114914. , Epub 2022 Nov 9. PMID:36410167<ref>PMID:36410167</ref>
-Description: Pim1 in complex with 4-((6-hydroxybenzofuran-3-yl)methyl)benzoic acid and Pimtide
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-[[Category: Unreleased Structures]]
+</div>
-[[Category: Heine, A]]
+<div class="pdbe-citations 8afr" style="background-color:#fffaf0;"></div>
-[[Category: Hochban, P.M.M]]
+== References ==
-[[Category: Diederich, W.E]]
+<references/>
+__TOC__
+</StructureSection>
+[[Category: Homo sapiens]]
+[[Category: Large Structures]]
+[[Category: Synthetic construct]]
+[[Category: Diederich WE]]
+[[Category: Heine A]]
+[[Category: Hochban PMM]]

8afr

From Proteopedia

Revision as of 11:19, 1 February 2023

Pim1 in complex with 4-((6-hydroxybenzofuran-3-yl)methyl)benzoic acid and Pimtide

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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