OCA at 06:30, 31 July 2019

OCA — Wed, 31 Jul 2019 06:30:14 GMT

←Older revision		Revision as of 06:30, 31 July 2019
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-	'''Unreleased structure'''

-	The entry ~~6quv~~ is ~~ON HOLD~~ ~~until Paper~~ Publication	+	==Crystal Structure of KRAS-G12D in complex with GMP-PCP and compound 15R==
		+	<StructureSection load='6quv' size='340' side='right'caption='[[6quv]], [[Resolution\|resolution]] 1.48Å' scene=''>
		+	== Structural highlights ==
		+	<table><tr><td colspan='2'>[[6quv]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6QUV OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6QUV FirstGlance]. <br>
		+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=GCP:PHOSPHOMETHYLPHOSPHONIC+ACID+GUANYLATE+ESTER'>GCP</scene>, <scene name='pdbligand=JJN:(6~{a}~{R},11~{b}~{S})-6~{a}-(1,4-dimethylpiperidin-4-yl)-7,11~{b}-dihydro-6~{H}-indolo[2,3-c]isoquinolin-5-one'>JJN</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</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=6quv FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6quv OCA], [http://pdbe.org/6quv PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6quv RCSB], [http://www.ebi.ac.uk/pdbsum/6quv PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6quv ProSAT]</span></td></tr>
		+	</table>
		+	== Disease ==
		+	[[http://www.uniprot.org/uniprot/RASK_HUMAN RASK_HUMAN]] Defects in KRAS are a cause of acute myelogenous leukemia (AML) [MIM:[http://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:[http://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:[http://omim.org/entry/609942 609942]]. Noonan syndrome (NS) [MIM:[http://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:[http://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:[http://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 ==
		+	[[http://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 ==
		+	Natural products have proven to be a rich source of molecular architectures for drugs. Here, an integrated approach to natural product screening is proposed, which uncovered eight new natural product scaffolds for KRAS-the most frequently mutated oncogenic driver in human cancers, which has remained thus far undrugged. The approach combines aspects of virtual screening, fragment-based screening, structure-activity relationships (SAR) by NMR, and structure-based drug discovery to overcome the limitations in traditional natural product approaches. By using our approach, a new "snugness of fit" scoring function and the first crystal-soaking system of the active form of KRAS(G12D) , the protein-ligand X-ray structures of a tricyclic indolopyrrole fungal alkaloid and an indoloisoquinolinone have been successfully elucidated. The natural product KRAS hits discovered provide fruitful ground for the optimization of highly potent natural-product-based inhibitors of the active form of oncogenic RAS. This integrated approach for screening natural products also holds promise for other "undruggable" targets.

-	~~Authors: Fischer~~, G., ~~Kessler~~, D., ~~Muellauer~~, B., ~~Wolkerstorfer~~, B.	+	KRAS Binders Hidden in Nature.,Bergner A, Cockcroft X, Fischer G, Gollner A, Hela W, Kousek R, Mantoulidis A, Martin LJ, Mayer M, Mullauer B, Siszler G, Wolkerstorfer B, Kessler D, McConnell DB Chemistry. 2019 Jun 23. doi: 10.1002/chem.201902810. PMID:31231840<ref>PMID:31231840</ref>

-	~~Description: Crystal Structure~~ of ~~KRAS~~-~~G12D in complex with GMP~~-~~PCP and compound 15R~~	+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
-	[[Category: ~~Unreleased~~ Structures]]	+	</div>
		+	<div class="pdbe-citations 6quv" style="background-color:#fffaf0;"></div>
		+	== References ==
		+	<references/>
		+	__TOC__
		+	</StructureSection>
		+	[[Category: Large Structures]]
	[[Category: Fischer, G]]		[[Category: Fischer, G]]
-	[[Category: Wolkerstorfer, B]]
	[[Category: Kessler, D]]		[[Category: Kessler, D]]
	[[Category: Muellauer, B]]		[[Category: Muellauer, B]]
		+	[[Category: Wolkerstorfer, B]]
		+	[[Category: Cancer]]
		+	[[Category: Gtpase]]
		+	[[Category: Kra]]
		+	[[Category: Oncoprotein]]
		+	[[Category: Ppi]]

OCA at 06:05, 20 March 2019

OCA — Wed, 20 Mar 2019 06:05:49 GMT

←Older revision		Revision as of 06:05, 20 March 2019
Line 1:		Line 1:
	'''Unreleased structure'''		'''Unreleased structure'''

-	The entry 6quv is ON HOLD	+	The entry 6quv is ON HOLD until Paper Publication

	Authors: Fischer, G., Kessler, D., Muellauer, B., Wolkerstorfer, B.		Authors: Fischer, G., Kessler, D., Muellauer, B., Wolkerstorfer, B.

-	Description: Crystal Structure of KRAS-G12D im complex with GMP-PCP	+	Description: Crystal Structure of KRAS-G12D in complex with GMP-PCP and compound 15R
	[[Category: Unreleased Structures]]		[[Category: Unreleased Structures]]
	[[Category: Fischer, G]]		[[Category: Fischer, G]]

OCA: Protected "6quv" [edit=sysop:move=sysop]

OCA — Wed, 06 Mar 2019 05:57:58 GMT

Protected "6quv" [edit=sysop:move=sysop]

←Older revision

Revision as of 05:57, 6 March 2019

OCA: New page: '''Unreleased structure''' The entry 6quv is ON HOLD Authors: Fischer, G., Kessler, D., Muellauer, B., Wolkerstorfer, B. Description: Crystal Structure of KRAS-G12D im complex with GMP...

OCA — Wed, 06 Mar 2019 05:57:56 GMT

New page: '''Unreleased structure''' The entry 6quv is ON HOLD Authors: Fischer, G., Kessler, D., Muellauer, B., Wolkerstorfer, B. Description: Crystal Structure of KRAS-G12D im complex with GMP...

New page

'''Unreleased structure'''

The entry 6quv is ON HOLD

Authors: Fischer, G., Kessler, D., Muellauer, B., Wolkerstorfer, B.

Description: Crystal Structure of KRAS-G12D im complex with GMP-PCP
[[Category: Unreleased Structures]]
[[Category: Fischer, G]]
[[Category: Wolkerstorfer, B]]
[[Category: Kessler, D]]
[[Category: Muellauer, B]]

6quv - Revision history

OCA at 06:30, 31 July 2019

OCA at 06:05, 20 March 2019

OCA: Protected "6quv" [edit=sysop:move=sysop]

OCA: New page: '''Unreleased structure''' The entry 6quv is ON HOLD Authors: Fischer, G., Kessler, D., Muellauer, B., Wolkerstorfer, B. Description: Crystal Structure of KRAS-G12D im complex with GMP...