View source for 9ymo


==Crystal Structure of human KRAS G12D in complex with GDP and AM-2383==
<StructureSection load='9ymo' size='340' side='right'caption='[[9ymo]], [[Resolution|resolution]] 1.25&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[9ymo]] 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=9YMO OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=9YMO 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]] 1.25&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=A1AG3:(3R)-1-[(7P)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-{[(2R,4R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-4-yl]-3-methylpiperidin-3-ol'>A1AG3</scene>, <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=SO4:SULFATE+ION'>SO4</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=9ymo FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=9ymo OCA], [https://pdbe.org/9ymo PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=9ymo RCSB], [https://www.ebi.ac.uk/pdbsum/9ymo PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=9ymo 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 ==
Therapeutically targeting mutant KRAS represents a clinically validated approach for the treatment of solid tumors, including lung, colon, and pancreatic cancers. The approval of covalent KRAS(G12C) inhibitors, such as sotorasib and adagrasib, has fueled intense interest in expanding KRAS-directed therapies to mutations beyond KRAS(G12C), such as KRAS(G12D), KRAS(G12V), and KRAS(G13D). Here, we describe the structure- and property-based design of reversible inhibitors of diverse oncogenic mutants of KRAS, leading to AM-2383, a pan-KRAS inhibitor that blocks signaling via both the GDP(off)- and GTP(on)-bound states of KRAS, while sparing the closely related RAS isoforms HRAS and NRAS. AM-2383 disrupts signaling downstream of KRAS, potently suppressing the growth of KRAS(G12D) and KRAS(G12V) tumor xenografts following oral administration. AM-2383 represents an important proof-of-concept that structural insights from prior covalent KRAS(G12C) inhibitors can be leveraged in the design of efficacious and well-tolerated inhibitors of diverse KRAS mutations.

Expanding Addressable KRAS Mutations through the Structure- and Property-Based Design of Dual-State (GDP/GTP), Reversible Pan-KRAS Inhibitors.,Wurz RP, Allen JR, Allen JG, Amegadzie A, Chen N, Eshon J, Li K, Li X, Li Y, Manoni F, Medina JM, Navaratne P, Pettus LH, Rahimoff R, Stellwagen J, Tercenio Q, Weires N, Wigman B, Yamano M, Zhao W, Husemoen G, Leth-Petersen S, Bauer D, Frohn MJ, Mukhina OA, Boursier M, Vaish A, Poppe L, Mohr C, Chen YC, Diaz GJ, Gaida K, Hughes PE, Khetan J, Mohn D, Osgood T, Saiki AY, Rex K, Verma R, Wang P, Rui H, Yu J, Dahal UP, Li Y, Agarwal P, Wegesser T, Lanman BA J Med Chem. 2026 Jul 14. doi: 10.1021/acs.jmedchem.6c01325. PMID:42446418<ref>PMID:42446418</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 9ymo" style="background-color:#fffaf0;"></div>
== References ==
<references/>
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</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Mohr C]]