View source for 7tlk


==Crystal Structure of K-Ras(G12S)==
<StructureSection load='7tlk' size='340' side='right'caption='[[7tlk]], [[Resolution|resolution]] 1.71&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[7tlk]] is a 2 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=7TLK OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7TLK FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.7110223&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GDP:GUANOSINE-5-DIPHOSPHATE'>GDP</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'>[https://proteopedia.org/fgij/fg.htm?mol=7tlk FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7tlk OCA], [https://pdbe.org/7tlk PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7tlk RCSB], [https://www.ebi.ac.uk/pdbsum/7tlk PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7tlk 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 ==
Drugs that directly impede the function of driver oncogenes offer exceptional efficacy and a therapeutic window. The recently approved mutant selective small-molecule cysteine-reactive covalent inhibitor of the G12C mutant of K-Ras, sotorasib, provides a case in point. KRAS is the most frequently mutated proto-oncogene in human cancer, yet despite success targeting the G12C allele, targeted therapy for other hotspot mutants of KRAS has not been described. Here we report the discovery of small molecules that covalently target a G12S somatic mutation in K-Ras and suppress its oncogenic signaling. We show that these molecules are active in cells expressing K-Ras(G12S) but spare the wild-type protein. Our results provide a path to targeting a second somatic mutation in the oncogene KRAS by overcoming the weak nucleophilicity of an acquired serine residue. The chemistry we describe may serve as a basis for the selective targeting of other unactivated serines.

Chemical acylation of an acquired serine suppresses oncogenic signaling of K-Ras(G12S).,Zhang Z, Guiley KZ, Shokat KM Nat Chem Biol. 2022 Jul 21. pii: 10.1038/s41589-022-01065-9. doi:, 10.1038/s41589-022-01065-9. PMID:35864332<ref>PMID:35864332</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 7tlk" style="background-color:#fffaf0;"></div>

==See Also==
*[[GTPase KRas 3D structures|GTPase KRas 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Guiley KZ]]
[[Category: Shokat KM]]
[[Category: Ziyang Z]]