8azz - Revision history

OCA at 08:15, 7 February 2024

OCA — Wed, 07 Feb 2024 08:15:14 GMT

←Older revision		Revision as of 08:15, 7 February 2024
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	== Function ==		== Function ==
	[https://www.uniprot.org/uniprot/RASK_HUMAN RASK_HUMAN] Ras proteins bind GDP/GTP and possess intrinsic GTPase activity.		[https://www.uniprot.org/uniprot/RASK_HUMAN RASK_HUMAN] Ras proteins bind GDP/GTP and possess intrinsic GTPase activity.
-	<div style="background-color:#fffaf0;">
-	== Publication Abstract from PubMed ==
-	KRAS is one of the most commonly mutated proteins in cancer, and efforts to directly inhibit its function have been continuing for decades. The most successful of these has been the development of covalent allele-specific inhibitors that trap KRAS G12C in its inactive conformation and suppress tumour growth in patients(1-7). Whether inactive-state selective inhibition can be used to therapeutically target non-G12C KRAS mutants remains under investigation. Here we report the discovery and characterization of a non-covalent inhibitor that binds preferentially and with high affinity to the inactive state of KRAS while sparing NRAS and HRAS. Although limited to only a few amino acids, the evolutionary divergence in the GTPase domain of RAS isoforms was sufficient to impart orthosteric and allosteric constraints for KRAS selectivity. The inhibitor blocked nucleotide exchange to prevent the activation of wild-type KRAS and a broad range of KRAS mutants, including G12A/C/D/F/V/S, G13C/D, V14I, L19F, Q22K, D33E, Q61H, K117N and A146V/T. Inhibition of downstream signalling and proliferation was restricted to cancer cells harbouring mutant KRAS, and drug treatment suppressed KRAS mutant tumour growth in mice, without having a detrimental effect on animal weight. Our study suggests that most KRAS oncoproteins cycle between an active state and an inactive state in cancer cells and are dependent on nucleotide exchange for activation. Pan-KRAS inhibitors, such as the one described here, have broad therapeutic implications and merit clinical investigation in patients with KRAS-driven cancers.
-
-	Pan-KRAS inhibitor disables oncogenic signalling and tumour growth.,Kim D, Herdeis L, Rudolph D, Zhao Y, Bottcher J, Vides A, Ayala-Santos CI, Pourfarjam Y, Cuevas-Navarro A, Xue JY, Mantoulidis A, Broker J, Wunberg T, Schaaf O, Popow J, Wolkerstorfer B, Kropatsch KG, Qu R, de Stanchina E, Sang B, Li C, McConnell DB, Kraut N, Lito P Nature. 2023 May 31. doi: 10.1038/s41586-023-06123-3. PMID:37258666<ref>PMID:37258666</ref>
-
-	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
-	</div>
-	<div class="pdbe-citations 8azz" style="background-color:#fffaf0;"></div>
	== References ==		== References ==
	<references/>		<references/>

OCA at 06:20, 19 July 2023

OCA — Wed, 19 Jul 2023 06:20:13 GMT

←Older revision		Revision as of 06:20, 19 July 2023
Line 4:		Line 4:
	== Structural highlights ==		== Structural highlights ==
	<table><tr><td colspan='2'>[[8azz]] 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=8AZZ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8AZZ FirstGlance]. <br>		<table><tr><td colspan='2'>[[8azz]] 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=8AZZ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8AZZ FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=GDP:GUANOSINE-5-DIPHOSPHATE'>GDP</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=OFU:(4S)-2-azanyl-4-methyl-4-[3-[4-[(1S)-1-[(2S)-1-methylpyrrolidin-1-ium-2-yl]ethoxy]pyrimidin-2-yl]-1,2,4-oxadiazol-5-yl]-6,7-dihydro-5H-1-benzothiophene-3-carbonitrile'>OFU</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]] 1.02Å</td></tr>
		+	<tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=GDP:GUANOSINE-5-DIPHOSPHATE'>GDP</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=OFU:(4S)-2-azanyl-4-methyl-4-[3-[4-[(1S)-1-[(2S)-1-methylpyrrolidin-1-ium-2-yl]ethoxy]pyrimidin-2-yl]-1,2,4-oxadiazol-5-yl]-6,7-dihydro-5H-1-benzothiophene-3-carbonitrile'>OFU</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=8azz FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8azz OCA], [https://pdbe.org/8azz PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8azz RCSB], [https://www.ebi.ac.uk/pdbsum/8azz PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8azz 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=8azz FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8azz OCA], [https://pdbe.org/8azz PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8azz RCSB], [https://www.ebi.ac.uk/pdbsum/8azz PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8azz ProSAT]</span></td></tr>
	</table>		</table>

OCA at 09:36, 21 June 2023

OCA — Wed, 21 Jun 2023 09:36:43 GMT

←Older revision		Revision as of 09:36, 21 June 2023
Line 1:		Line 1:
-	'''Unreleased structure'''

-	The entry ~~8azz~~ is ~~ON HOLD~~	+	==KRAS-G12V in complex with BI-2865==
		+	<StructureSection load='8azz' size='340' side='right'caption='[[8azz]], [[Resolution\|resolution]] 1.02Å' scene=''>
		+	== Structural highlights ==
		+	<table><tr><td colspan='2'>[[8azz]] 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=8AZZ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8AZZ FirstGlance]. <br>
		+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=GDP:GUANOSINE-5-DIPHOSPHATE'>GDP</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=OFU:(4S)-2-azanyl-4-methyl-4-[3-[4-[(1S)-1-[(2S)-1-methylpyrrolidin-1-ium-2-yl]ethoxy]pyrimidin-2-yl]-1,2,4-oxadiazol-5-yl]-6,7-dihydro-5H-1-benzothiophene-3-carbonitrile'>OFU</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=8azz FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8azz OCA], [https://pdbe.org/8azz PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8azz RCSB], [https://www.ebi.ac.uk/pdbsum/8azz PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8azz ProSAT]</span></td></tr>
		+	</table>
		+	== Disease ==
		+	[https://www.uniprot.org/uniprot/RASK_HUMAN RASK_HUMAN] Defects in KRAS are a cause of acute myelogenous leukemia (AML) [MIM:[https://omim.org/entry/601626 601626]. AML is a malignant disease in which hematopoietic precursors are arrested in an early stage of development.<ref>PMID:8955068</ref> Defects in KRAS are a cause of juvenile myelomonocytic leukemia (JMML) [MIM:[https://omim.org/entry/607785 607785]. JMML is a pediatric myelodysplastic syndrome that constitutes approximately 30% of childhood cases of myelodysplastic syndrome (MDS) and 2% of leukemia. It is characterized by leukocytosis with tissue infiltration and in vitro hypersensitivity of myeloid progenitors to granulocyte-macrophage colony stimulating factor. Defects in KRAS are the cause of Noonan syndrome type 3 (NS3) [MIM:[https://omim.org/entry/609942 609942]. Noonan syndrome (NS) [MIM:[https://omim.org/entry/163950 163950] is a disorder characterized by dysmorphic facial features, short stature, hypertelorism, cardiac anomalies, deafness, motor delay, and a bleeding diathesis. It is a genetically heterogeneous and relatively common syndrome, with an estimated incidence of 1 in 1000-2500 live births. Rarely, NS is associated with juvenile myelomonocytic leukemia (JMML). NS3 inheritance is autosomal dominant.<ref>PMID:16773572</ref> <ref>PMID:16474405</ref> <ref>PMID:17468812</ref> <ref>PMID:17056636</ref> <ref>PMID:19396835</ref> <ref>PMID:20949621</ref> Defects in KRAS are a cause of gastric cancer (GASC) [MIM:[https://omim.org/entry/613659 613659]; also called gastric cancer intestinal or stomach cancer. Gastric cancer is a malignant disease which starts in the stomach, can spread to the esophagus or the small intestine, and can extend through the stomach wall to nearby lymph nodes and organs. It also can metastasize to other parts of the body. The term gastric cancer or gastric carcinoma refers to adenocarcinoma of the stomach that accounts for most of all gastric malignant tumors. Two main histologic types are recognized, diffuse type and intestinal type carcinomas. Diffuse tumors are poorly differentiated infiltrating lesions, resulting in thickening of the stomach. In contrast, intestinal tumors are usually exophytic, often ulcerating, and associated with intestinal metaplasia of the stomach, most often observed in sporadic disease.<ref>PMID:3034404</ref> <ref>PMID:7773929</ref> <ref>PMID:14534542</ref> Note=Defects in KRAS are a cause of pylocytic astrocytoma (PA). Pylocytic astrocytomas are neoplasms of the brain and spinal cord derived from glial cells which vary from histologically benign forms to highly anaplastic and malignant tumors.<ref>PMID:8439212</ref> Defects in KRAS are a cause of cardiofaciocutaneous syndrome (CFC syndrome) [MIM:[https://omim.org/entry/115150 115150]; also known as cardio-facio-cutaneous syndrome. CFC syndrome is characterized by a distinctive facial appearance, heart defects and mental retardation. Heart defects include pulmonic stenosis, atrial septal defects and hypertrophic cardiomyopathy. Some affected individuals present with ectodermal abnormalities such as sparse, friable hair, hyperkeratotic skin lesions and a generalized ichthyosis-like condition. Typical facial features are similar to Noonan syndrome. They include high forehead with bitemporal constriction, hypoplastic supraorbital ridges, downslanting palpebral fissures, a depressed nasal bridge, and posteriorly angulated ears with prominent helices. The inheritance of CFC syndrome is autosomal dominant. Note=KRAS mutations are involved in cancer development.
		+	== Function ==
		+	[https://www.uniprot.org/uniprot/RASK_HUMAN RASK_HUMAN] Ras proteins bind GDP/GTP and possess intrinsic GTPase activity.
		+	<div style="background-color:#fffaf0;">
		+	== Publication Abstract from PubMed ==
		+	KRAS is one of the most commonly mutated proteins in cancer, and efforts to directly inhibit its function have been continuing for decades. The most successful of these has been the development of covalent allele-specific inhibitors that trap KRAS G12C in its inactive conformation and suppress tumour growth in patients(1-7). Whether inactive-state selective inhibition can be used to therapeutically target non-G12C KRAS mutants remains under investigation. Here we report the discovery and characterization of a non-covalent inhibitor that binds preferentially and with high affinity to the inactive state of KRAS while sparing NRAS and HRAS. Although limited to only a few amino acids, the evolutionary divergence in the GTPase domain of RAS isoforms was sufficient to impart orthosteric and allosteric constraints for KRAS selectivity. The inhibitor blocked nucleotide exchange to prevent the activation of wild-type KRAS and a broad range of KRAS mutants, including G12A/C/D/F/V/S, G13C/D, V14I, L19F, Q22K, D33E, Q61H, K117N and A146V/T. Inhibition of downstream signalling and proliferation was restricted to cancer cells harbouring mutant KRAS, and drug treatment suppressed KRAS mutant tumour growth in mice, without having a detrimental effect on animal weight. Our study suggests that most KRAS oncoproteins cycle between an active state and an inactive state in cancer cells and are dependent on nucleotide exchange for activation. Pan-KRAS inhibitors, such as the one described here, have broad therapeutic implications and merit clinical investigation in patients with KRAS-driven cancers.

-	~~Authors~~:	+	Pan-KRAS inhibitor disables oncogenic signalling and tumour growth.,Kim D, Herdeis L, Rudolph D, Zhao Y, Bottcher J, Vides A, Ayala-Santos CI, Pourfarjam Y, Cuevas-Navarro A, Xue JY, Mantoulidis A, Broker J, Wunberg T, Schaaf O, Popow J, Wolkerstorfer B, Kropatsch KG, Qu R, de Stanchina E, Sang B, Li C, McConnell DB, Kraut N, Lito P Nature. 2023 May 31. doi: 10.1038/s41586-023-06123-3. PMID:37258666<ref>PMID:37258666</ref>

-	~~Description~~:	+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
-	[[Category: ~~Unreleased~~ Structures]]	+	</div>
		+	<div class="pdbe-citations 8azz" style="background-color:#fffaf0;"></div>
		+	== References ==
		+	<references/>
		+	__TOC__
		+	</StructureSection>
		+	[[Category: Homo sapiens]]
		+	[[Category: Large Structures]]
		+	[[Category: Boettcher J]]
		+	[[Category: Herdeis L]]

OCA at 06:15, 14 June 2023

OCA — Wed, 14 Jun 2023 06:15:14 GMT

←Older revision		Revision as of 06:15, 14 June 2023
Line 1:		Line 1:
	'''Unreleased structure'''		'''Unreleased structure'''

-	The entry 8azz is ON HOLD ~~until Paper Publication~~	+	The entry 8azz is ON HOLD

	Authors:		Authors:

OCA at 16:43, 19 October 2022

OCA — Wed, 19 Oct 2022 16:43:22 GMT

←Older revision		Revision as of 16:43, 19 October 2022
Line 1:		Line 1:
	'''Unreleased structure'''		'''Unreleased structure'''

-	The entry 8azz is ON HOLD	+	The entry 8azz is ON HOLD until Paper Publication

	Authors:		Authors:

OCA: Protected "8azz" [edit=sysop:move=sysop]

OCA — Wed, 14 Sep 2022 05:41:01 GMT

Protected "8azz" [edit=sysop:move=sysop]

←Older revision

Revision as of 05:41, 14 September 2022

OCA: New page: '''Unreleased structure''' The entry 8azz is ON HOLD Authors: Description: Category: Unreleased Structures

OCA — Wed, 14 Sep 2022 05:41:00 GMT

New page: '''Unreleased structure''' The entry 8azz is ON HOLD Authors: Description: Category: Unreleased Structures

New page

'''Unreleased structure'''

The entry 8azz is ON HOLD

Authors:

Description:
[[Category: Unreleased Structures]]