7m0k - Revision history

OCA at 15:01, 6 March 2024

OCA — Wed, 06 Mar 2024 15:01:07 GMT

←Older revision		Revision as of 15:01, 6 March 2024
Line 3:		Line 3:
	<StructureSection load='7m0k' size='340' side='right'caption='[[7m0k]], [[Resolution\|resolution]] 2.01Å' scene=''>		<StructureSection load='7m0k' size='340' side='right'caption='[[7m0k]], [[Resolution\|resolution]] 2.01Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[7m0k]] 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=7M0K OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7M0K FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[7m0k]] 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=7M0K OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7M0K FirstGlance]. <br>
-	</td></tr><tr id='~~ligand~~'><td class="sblockLbl"><b>[[~~Ligand~~\|~~Ligands~~:]]</b></td><td class="sblockDat" id="~~ligandDat~~">~~<scene name='pdbligand=YK7:4-anilino-2~~-[~~(6-methoxy-~~2~~-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)amino]pyrimidine-5-carboxamide'>YK7</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]] 2.01Å</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=YK7:4-anilino-2-[(6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)amino]pyrimidine-5-carboxamide'>YK7</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=7m0k FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7m0k OCA], [https://pdbe.org/7m0k PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7m0k RCSB], [https://www.ebi.ac.uk/pdbsum/7m0k PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7m0k 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=7m0k FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7m0k OCA], [https://pdbe.org/7m0k PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7m0k RCSB], [https://www.ebi.ac.uk/pdbsum/7m0k PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7m0k 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 1 (HPK1), a serine/threonine kinase, is a negative immune regulator of T cell receptor (TCR) and B cell signaling that is primarily expressed in hematopoietic cells. Accordingly, it has been reported that HPK1 loss-of-function in HPK1 kinase-dead syngeneic mouse models shows enhanced T cell signaling and cytokine production as well as tumor growth inhibition in vivo, supporting its value as an immunotherapeutic target. Herein, we present the structurally enabled discovery of novel, potent, and selective diaminopyrimidine carboxamide HPK1 inhibitors. The key discovery of a carboxamide moiety was essential for enhanced enzyme inhibitory potency and kinome selectivity as well as sustained elevation of cellular IL-2 production across a titration range in human peripheral blood mononuclear cells. The elucidation of structure-activity relationships using various pendant amino ring systems allowed for the identification of several small molecule type-I inhibitors with promising in vitro profiles.	+
-		+
-	Discovery of Diaminopyrimidine Carboxamide HPK1 Inhibitors as Preclinical Immunotherapy Tool Compounds.,Vara BA, Levi SM, Achab A, Candito DA, Fradera X, Lesburg CA, Kawamura S, Lacey BM, Lim J, Methot JL, Xu Z, Xu H, Smith DM, Piesvaux JA, Miller JR, Bittinger M, Ranganath SH, Bennett DJ, DiMauro EF, Pasternak A ACS Med Chem Lett. 2021 Mar 19;12(4):653-661. doi:, 10.1021/acsmedchemlett.1c00096. eCollection 2021 Apr 8. PMID:33859804<ref>PMID:33859804</ref>	+
-		+
-	~~From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>~~	+
-	~~</div>~~	+
-	~~<div class="pdbe-citations 7m0k" 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: Transferase]]~~	+
-	~~[[Category: Transferase-transferase inhibitor complex~~]]	+

OCA at 09:15, 5 May 2021

OCA — Wed, 05 May 2021 09:15:17 GMT

←Older revision		Revision as of 09:15, 5 May 2021
Line 1:		Line 1:

	==HPK1 IN COMPLEX WITH COMPOUND 1==		==HPK1 IN COMPLEX WITH COMPOUND 1==
-	<StructureSection load='7m0k' size='340' side='right'caption='[[7m0k]]' scene=''>	+	<StructureSection load='7m0k' size='340' side='right'caption='[[7m0k]], [[Resolution\|resolution]] 2.01Å' 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=7M0K OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7M0K FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[7m0k]] 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=7M0K OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7M0K 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=7m0k FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7m0k OCA], [https://pdbe.org/7m0k PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7m0k RCSB], [https://www.ebi.ac.uk/pdbsum/7m0k PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7m0k 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=YK7:4-anilino-2-[(6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)amino]pyrimidine-5-carboxamide'>YK7</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=7m0k FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7m0k OCA], [https://pdbe.org/7m0k PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7m0k RCSB], [https://www.ebi.ac.uk/pdbsum/7m0k PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7m0k 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 1 (HPK1), a serine/threonine kinase, is a negative immune regulator of T cell receptor (TCR) and B cell signaling that is primarily expressed in hematopoietic cells. Accordingly, it has been reported that HPK1 loss-of-function in HPK1 kinase-dead syngeneic mouse models shows enhanced T cell signaling and cytokine production as well as tumor growth inhibition in vivo, supporting its value as an immunotherapeutic target. Herein, we present the structurally enabled discovery of novel, potent, and selective diaminopyrimidine carboxamide HPK1 inhibitors. The key discovery of a carboxamide moiety was essential for enhanced enzyme inhibitory potency and kinome selectivity as well as sustained elevation of cellular IL-2 production across a titration range in human peripheral blood mononuclear cells. The elucidation of structure-activity relationships using various pendant amino ring systems allowed for the identification of several small molecule type-I inhibitors with promising in vitro profiles.
		+
		+	Discovery of Diaminopyrimidine Carboxamide HPK1 Inhibitors as Preclinical Immunotherapy Tool Compounds.,Vara BA, Levi SM, Achab A, Candito DA, Fradera X, Lesburg CA, Kawamura S, Lacey BM, Lim J, Methot JL, Xu Z, Xu H, Smith DM, Piesvaux JA, Miller JR, Bittinger M, Ranganath SH, Bennett DJ, DiMauro EF, Pasternak A ACS Med Chem Lett. 2021 Mar 19;12(4):653-661. doi:, 10.1021/acsmedchemlett.1c00096. eCollection 2021 Apr 8. PMID:33859804<ref>PMID:33859804</ref>
		+
		+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
		+	</div>
		+	<div class="pdbe-citations 7m0k" 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: Transferase]]
		+	[[Category: Transferase-transferase inhibitor complex]]

OCA at 06:53, 7 April 2021

OCA — Wed, 07 Apr 2021 06:53:50 GMT

←Older revision		Revision as of 06:53, 7 April 2021
Line 1:		Line 1:
-	'''Unreleased structure'''

-	~~The entry~~ 7m0k ~~is ON HOLD~~	+	==HPK1 IN COMPLEX WITH COMPOUND 1==
-		+	<StructureSection load='7m0k' size='340' side='right'caption='[[7m0k]]' scene=''>
-	~~Authors~~:	+	== Structural highlights ==
-		+	<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7M0K OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7M0K 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=7m0k FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7m0k OCA], [https://pdbe.org/7m0k PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7m0k RCSB], [https://www.ebi.ac.uk/pdbsum/7m0k PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7m0k ProSAT]</span></td></tr>
-	[[Category: ~~Unreleased~~ Structures]]	+	</table>
		+	__TOC__
		+	</StructureSection>
		+	[[Category: Large Structures]]
		+	[[Category: Lesburg CA]]

OCA: Protected "7m0k" [edit=sysop:move=sysop]

OCA — Wed, 17 Mar 2021 05:28:22 GMT

Protected "7m0k" [edit=sysop:move=sysop]

←Older revision

Revision as of 05:28, 17 March 2021

OCA: New page: '''Unreleased structure''' The entry 7m0k is ON HOLD Authors: Description: Category: Unreleased Structures

OCA — Wed, 17 Mar 2021 05:28:21 GMT

New page: '''Unreleased structure''' The entry 7m0k is ON HOLD Authors: Description: Category: Unreleased Structures

New page

'''Unreleased structure'''

The entry 7m0k is ON HOLD

Authors:

Description:
[[Category: Unreleased Structures]]