7l24 - Revision history

OCA at 14:58, 6 March 2024

OCA — Wed, 06 Mar 2024 14:58:32 GMT

←Older revision		Revision as of 14:58, 6 March 2024
Line 3:		Line 3:
	<StructureSection load='7l24' size='340' side='right'caption='[[7l24]], [[Resolution\|resolution]] 2.68Å' scene=''>		<StructureSection load='7l24' size='340' side='right'caption='[[7l24]], [[Resolution\|resolution]] 2.68Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[7l24]] 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=7L24 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7L24 FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[7l24]] 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=7L24 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7L24 FirstGlance]. <br>
-	</td></tr><tr id='~~ligand~~'><td class="sblockLbl"><b>[[~~Ligand~~\|~~Ligands~~:]]</b></td><td class="sblockDat" id="~~ligandDat~~">~~<scene name='pdbligand=XHV:6-(2-fluoro-6-methoxyphenyl)-1~~-[~~4-(4-methylpiperazin-1-yl)phenyl]-1H-pyrazolo~~[~~4,3-c~~]~~pyridine'>XHV</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]] 2.68Å</td></tr>
-	<tr id='~~gene~~'><td class="sblockLbl"><b>[[~~Gene~~\|~~Gene~~:]]</b></td><td class="sblockDat"~~>MAP4K1, HPK1 ([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=XHV:6-(2-fluoro-6-methoxyphenyl)-1-[4-(4-methylpiperazin-1-yl)phenyl]-1H-pyrazolo[4,3-c]pyridine'>XHV</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=7l24 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7l24 OCA], [https://pdbe.org/7l24 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7l24 RCSB], [https://www.ebi.ac.uk/pdbsum/7l24 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7l24 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=7l24 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7l24 OCA], [https://pdbe.org/7l24 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7l24 RCSB], [https://www.ebi.ac.uk/pdbsum/7l24 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7l24 ProSAT]</span></td></tr>
	</table>		</table>
	== Function ==		== Function ==
-	[[https://www.uniprot.org/uniprot/M4K1_HUMAN M4K1_HUMAN]] Serine/threonine-protein kinase, which may play a role in the response to environmental stress. Appears to act upstream of the JUN N-terminal pathway. May play a role in hematopoietic lineage decisions and growth regulation. Able to autophosphorylate.<ref>PMID:24362026</ref> <ref>PMID:8824585</ref>	+	[https://www.uniprot.org/uniprot/M4K1_HUMAN M4K1_HUMAN] Serine/threonine-protein kinase, which may play a role in the response to environmental stress. Appears to act upstream of the JUN N-terminal pathway. May play a role in hematopoietic lineage decisions and growth regulation. Able to autophosphorylate.<ref>PMID:24362026</ref> <ref>PMID:8824585</ref>
-	~~<div style="background-color:#fffaf0;">~~	+
-	~~== Publication Abstract from PubMed ==~~	+
-	Hematopoietic progenitor kinase (HPK1), a negative regulator of TCR-mediated T-cell activation, has been recognized as a novel antitumor immunotherapy target. Structural optimization of kinase inhibitor 4 through a systematic two-dimensional diversity screen of pyrazolopyridines led to the identification of potent and selective compounds. Crystallographic studies with HPK1 revealed a favorable water-mediated interaction with Asp155 and a salt bridge to Asp101 with optimized heterocyclic solvent fronts that were critical for enhanced potency and selectivity. Computational studies of model systems revealed differences in torsional profiles that allowed for these beneficial protein-ligand interactions. Further optimization of molecular properties led to identification of potent and selective reverse indazole inhibitor 36 that inhibited phosphorylation of adaptor protein SLP76 in human PBMC and exhibited low clearance with notable bioavailability in in vivo rat studies.	+
-		+
-	Identification of Potent Reverse Indazole Inhibitors for HPK1.,Yu EC, Methot JL, Fradera X, Lesburg CA, Lacey BM, Siliphaivanh P, Liu P, Smith DM, Xu Z, Piesvaux JA, Kawamura S, Xu H, Miller JR, Bittinger M, Pasternak A ACS Med Chem Lett. 2021 Mar 1;12(3):459-466. doi: 10.1021/acsmedchemlett.0c00672., eCollection 2021 Mar 11. PMID:33738073<ref>PMID:33738073</ref>	+
-		+
-	~~From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>~~	+
-	~~</div>~~	+
-	~~<div class="pdbe-citations 7l24" style="background-color:#fffaf0;"></div~~>	+
	== References ==		== References ==
	<references/>		<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
-	[[Category: ~~Human~~]]	+	[[Category: Homo sapiens]]
	[[Category: Large Structures]]		[[Category: Large Structures]]
-	~~[[Category: Non-specific serine/threonine protein kinase]]~~	+	[[Category: Lesburg CA]]
-	[[Category: Lesburg~~, C A]]~~	+
-	~~[[Category: Hpk1 hematopoietic progenitor kinase]]~~	+
-	~~[[Category: Inhibitor complex]]~~	+
-	~~[[Category: Transferase~~]]	+

OCA at 10:52, 31 March 2021

OCA — Wed, 31 Mar 2021 10:52:29 GMT

←Older revision		Revision as of 10:52, 31 March 2021
Line 1:		Line 1:

	==HPK1 IN COMPLEX WITH COMPOUND 11==		==HPK1 IN COMPLEX WITH COMPOUND 11==
-	<StructureSection load='7l24' size='340' side='right'caption='[[7l24]]' scene=''>	+	<StructureSection load='7l24' size='340' side='right'caption='[[7l24]], [[Resolution\|resolution]] 2.68Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7L24 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7L24 FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[7l24]] 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=7L24 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7L24 FirstGlance]. <br>
-	</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=7l24 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7l24 OCA], [https://pdbe.org/7l24 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7l24 RCSB], [https://www.ebi.ac.uk/pdbsum/7l24 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7l24 ProSAT]</span></td></tr>	+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=XHV:6-(2-fluoro-6-methoxyphenyl)-1-[4-(4-methylpiperazin-1-yl)phenyl]-1H-pyrazolo[4,3-c]pyridine'>XHV</scene></td></tr>
		+	<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">MAP4K1, HPK1 ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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=7l24 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7l24 OCA], [https://pdbe.org/7l24 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7l24 RCSB], [https://www.ebi.ac.uk/pdbsum/7l24 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7l24 ProSAT]</span></td></tr>
	</table>		</table>
		+	== Function ==
		+	[[https://www.uniprot.org/uniprot/M4K1_HUMAN M4K1_HUMAN]] Serine/threonine-protein kinase, which may play a role in the response to environmental stress. Appears to act upstream of the JUN N-terminal pathway. May play a role in hematopoietic lineage decisions and growth regulation. Able to autophosphorylate.<ref>PMID:24362026</ref> <ref>PMID:8824585</ref>
		+	<div style="background-color:#fffaf0;">
		+	== Publication Abstract from PubMed ==
		+	Hematopoietic progenitor kinase (HPK1), a negative regulator of TCR-mediated T-cell activation, has been recognized as a novel antitumor immunotherapy target. Structural optimization of kinase inhibitor 4 through a systematic two-dimensional diversity screen of pyrazolopyridines led to the identification of potent and selective compounds. Crystallographic studies with HPK1 revealed a favorable water-mediated interaction with Asp155 and a salt bridge to Asp101 with optimized heterocyclic solvent fronts that were critical for enhanced potency and selectivity. Computational studies of model systems revealed differences in torsional profiles that allowed for these beneficial protein-ligand interactions. Further optimization of molecular properties led to identification of potent and selective reverse indazole inhibitor 36 that inhibited phosphorylation of adaptor protein SLP76 in human PBMC and exhibited low clearance with notable bioavailability in in vivo rat studies.
		+
		+	Identification of Potent Reverse Indazole Inhibitors for HPK1.,Yu EC, Methot JL, Fradera X, Lesburg CA, Lacey BM, Siliphaivanh P, Liu P, Smith DM, Xu Z, Piesvaux JA, Kawamura S, Xu H, Miller JR, Bittinger M, Pasternak A ACS Med Chem Lett. 2021 Mar 1;12(3):459-466. doi: 10.1021/acsmedchemlett.0c00672., eCollection 2021 Mar 11. PMID:33738073<ref>PMID:33738073</ref>
		+
		+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
		+	</div>
		+	<div class="pdbe-citations 7l24" style="background-color:#fffaf0;"></div>
		+	== References ==
		+	<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
		+	[[Category: Human]]
	[[Category: Large Structures]]		[[Category: Large Structures]]
-	[[Category: Lesburg CA]]	+	[[Category: Non-specific serine/threonine protein kinase]]
		+	[[Category: Lesburg, C A]]
		+	[[Category: Hpk1 hematopoietic progenitor kinase]]
		+	[[Category: Inhibitor complex]]
		+	[[Category: Transferase]]

OCA at 06:48, 17 March 2021

OCA — Wed, 17 Mar 2021 06:48:46 GMT

←Older revision		Revision as of 06:48, 17 March 2021
Line 1:		Line 1:
-	'''Unreleased structure'''

-	~~The entry~~ 7l24 ~~is ON HOLD until Paper Publication~~	+	==HPK1 IN COMPLEX WITH COMPOUND 11==
-		+	<StructureSection load='7l24' size='340' side='right'caption='[[7l24]]' scene=''>
-	~~Authors~~:	+	== Structural highlights ==
-		+	<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7L24 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7L24 FirstGlance]. <br>
-	~~Description~~:	+	</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=7l24 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7l24 OCA], [https://pdbe.org/7l24 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7l24 RCSB], [https://www.ebi.ac.uk/pdbsum/7l24 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7l24 ProSAT]</span></td></tr>
-	[[Category: ~~Unreleased~~ Structures]]	+	</table>
		+	__TOC__
		+	</StructureSection>
		+	[[Category: Large Structures]]
		+	[[Category: Lesburg CA]]

OCA at 05:28, 30 December 2020

OCA — Wed, 30 Dec 2020 05:28:21 GMT

←Older revision		Revision as of 05:28, 30 December 2020
Line 1:		Line 1:
	'''Unreleased structure'''		'''Unreleased structure'''

-	The entry 7l24 is ON HOLD	+	The entry 7l24 is ON HOLD until Paper Publication

	Authors:		Authors:

OCA: Protected "7l24" [edit=sysop:move=sysop]

OCA — Thu, 24 Dec 2020 08:10:44 GMT

Protected "7l24" [edit=sysop:move=sysop]

←Older revision

Revision as of 08:10, 24 December 2020

OCA: New page: '''Unreleased structure''' The entry 7l24 is ON HOLD Authors: Description: Category: Unreleased Structures

OCA — Thu, 24 Dec 2020 08:10:43 GMT

New page: '''Unreleased structure''' The entry 7l24 is ON HOLD Authors: Description: Category: Unreleased Structures

New page

'''Unreleased structure'''

The entry 7l24 is ON HOLD

Authors:

Description:
[[Category: Unreleased Structures]]