9e9h
From Proteopedia
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| - | '''Unreleased structure''' | ||
| - | The entry | + | ==Crystal structure of human KRAS G12C covalently bound to DEL triazine compound 5== |
| + | <StructureSection load='9e9h' size='340' side='right'caption='[[9e9h]], [[Resolution|resolution]] 1.65Å' scene=''> | ||
| + | == Structural highlights == | ||
| + | <table><tr><td colspan='2'>[[9e9h]] 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=9E9H OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=9E9H 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]] 1.65Å</td></tr> | ||
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=A1BH6:(3~{S})-~{N},5-dimethyl-3-[[4-(3-morpholin-4-ylphenyl)-6-(2-propanoyl-2,7-diazaspiro[3.4]octan-7-yl)-1,3,5-triazin-2-yl]amino]hexanamide'>A1BH6</scene>, <scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=GDP:GUANOSINE-5-DIPHOSPHATE'>GDP</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=9e9h FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=9e9h OCA], [https://pdbe.org/9e9h PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=9e9h RCSB], [https://www.ebi.ac.uk/pdbsum/9e9h PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=9e9h 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 == | ||
| + | Covalent inhibition of the KRAS(G12C) oncoprotein has emerged as a promising therapeutic approach for the treatment of nonsmall cell lung cancer (NSCLC). The identification of KRAS(G12C) inhibitors has typically relied on the high-throughput screening (HTS) of libraries of cysteine-reactive small molecules or on the attachment of cysteine-reactive warheads to noncovalent binders of KRAS. Such screening approaches have historically been limited in the size and diversity of molecules that could be effectively screened. DNA-encoded library (DEL) screening has emerged as a promising approach to accelerate the preparation and screening of incredibly large and diverse chemical libraries. Here, we describe the design and synthesis of a covalent DEL to screen approximately 16 million compounds against KRAS(G12C). We additionally describe the hit identification, validation, and structure-based optimization that culminated in the identification of a series of structurally novel, potent, and selective covalent inhibitors of KRAS(G12C) with good pharmacokinetic profiles and promising in vivo pharmacodynamic effects. | ||
| - | + | Identification of Structurally Novel KRAS(G12C) Inhibitors through Covalent DNA-Encoded Library Screening.,Huang D, Manoni F, Sun Z, Liu R, Allen JR, Banerjee A, Cee VJ, Eshon J, Frohn MJ, Kaller MR, Lee H, Li C, Li X, Lopez P, Ma V, Medina JM, Mohr C, Mukhina OA, Pickrell AJ, Stellwagen J, Wu W, Zhang W, Zhu K, Dahal UP, Hu LA, Leavitt M, Li W, Li Y, Ma Y, Rex K, Saiki AY, Wang P, Sun Y, Dai D, Tamayo NA, Lanman BA J Med Chem. 2025 Feb 11. doi: 10.1021/acs.jmedchem.4c03071. PMID:39930787<ref>PMID:39930787</ref> | |
| - | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |
| - | [[Category: | + | </div> |
| - | [[Category: Mohr | + | <div class="pdbe-citations 9e9h" style="background-color:#fffaf0;"></div> |
| + | == References == | ||
| + | <references/> | ||
| + | __TOC__ | ||
| + | </StructureSection> | ||
| + | [[Category: Homo sapiens]] | ||
| + | [[Category: Large Structures]] | ||
| + | [[Category: Mohr C]] | ||
Current revision
Crystal structure of human KRAS G12C covalently bound to DEL triazine compound 5
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