7kyz

From Proteopedia

(Difference between revisions)

Current revision

Solution structures of full-length K-RAS bound to GDP

Structural highlights

7kyz is a 1 chain structure with sequence from Homo sapiens. Full experimental information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	Solution NMR, 20 models
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

RASK_HUMAN Defects in KRAS are a cause of acute myelogenous leukemia (AML) [MIM:601626. AML is a malignant disease in which hematopoietic precursors are arrested in an early stage of development.^[1] Defects in KRAS are a cause of juvenile myelomonocytic leukemia (JMML) [MIM: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:609942. Noonan syndrome (NS) [MIM: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.^[2] ^[3] ^[4] ^[5] ^[6] ^[7] Defects in KRAS are a cause of gastric cancer (GASC) [MIM: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.^[8] ^[9] ^[10] 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.^[11] Defects in KRAS are a cause of cardiofaciocutaneous syndrome (CFC syndrome) [MIM: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

RASK_HUMAN Ras proteins bind GDP/GTP and possess intrinsic GTPase activity.

Publication Abstract from PubMed

RAS is the most frequently mutated oncogene in cancer. RAS proteins show high sequence similarities in their G-domains but are significantly different in their C-terminal hypervariable regions (HVR). These regions interact with the cell membrane via lipid anchors that result from posttranslational modifications (PTM) of cysteine residues. KRAS4b is unique as it has only one cysteine that undergoes PTM, C185. Small molecule covalent modification of C185 would block any form of prenylation and subsequently inhibit attachment of KRAS4b to the cell membrane, blocking its biological activity. We translated this concept to the discovery and development of disulfide tethering screen hits into irreversible covalent modifiers of C185. These compounds inhibited proliferation of KRAS4b-driven mouse embryonic fibroblasts, but not cells driven by N-myristoylated KRAS4b that harbor a C185S mutation and are not dependent on C185 prenylation. Top-down proteomics was used to confirm target engagement in cells. These compounds bind in a pocket formed when the HVR folds back between helix 3 and 4 in the G-domain (HVR-alpha3-alpha4). This interaction can happen in the absence of small molecules as predicted by molecular dynamics simulations and is stabilized in the presence of C185 binders as confirmed by small-angle X-ray scattering and solution NMR. NOESY-HSQC, an NMR approach that measures internuclear distances of 6 A or less, and structure analysis identified the critical residues and interactions that define the HVR-alpha3-alpha4 pocket. Further development of compounds that bind to this pocket could be the basis of a new approach to targeting KRAS cancers.

Blocking C-terminal processing of KRAS4b via a direct covalent attack on the CaaX-box cysteine.,Maciag AE, Yang Y, Sharma AK, Turner DM, DeHart CJ, Abdelkarim H, Fan L, Smith BP, Kumari V, Dyba M, Rigby M, Castillo Badillo JA, Adams L, Fornelli L, Fox S, Brafman A, Turbyville T, Gillette W, Messing S, Agamasu C, Wolfe AL, Gysin S, Chan AH, Simanshu DK, Esposito D, Chertov O, Stephen AG, Arkin M, Renslo A, Kelleher NL, Gaponenko V, Lightstone FC, Nissley DV, McCormick F Proc Natl Acad Sci U S A. 2025 May 13;122(19):e2410766122. doi: , 10.1073/pnas.2410766122. Epub 2025 May 9. PMID:40343987^[12]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Bollag G, Adler F, elMasry N, McCabe PC, Conner E Jr, Thompson P, McCormick F, Shannon K. Biochemical characterization of a novel KRAS insertion mutation from a human leukemia. J Biol Chem. 1996 Dec 20;271(51):32491-4. PMID:8955068
↑ Carta C, Pantaleoni F, Bocchinfuso G, Stella L, Vasta I, Sarkozy A, Digilio C, Palleschi A, Pizzuti A, Grammatico P, Zampino G, Dallapiccola B, Gelb BD, Tartaglia M. Germline missense mutations affecting KRAS Isoform B are associated with a severe Noonan syndrome phenotype. Am J Hum Genet. 2006 Jul;79(1):129-35. Epub 2006 May 1. PMID:16773572 doi:10.1086/504394
↑ Schubbert S, Zenker M, Rowe SL, Boll S, Klein C, Bollag G, van der Burgt I, Musante L, Kalscheuer V, Wehner LE, Nguyen H, West B, Zhang KY, Sistermans E, Rauch A, Niemeyer CM, Shannon K, Kratz CP. Germline KRAS mutations cause Noonan syndrome. Nat Genet. 2006 Mar;38(3):331-6. Epub 2006 Feb 12. PMID:16474405 doi:ng1748
↑ Bertola DR, Pereira AC, Brasil AS, Albano LM, Kim CA, Krieger JE. Further evidence of genetic heterogeneity in Costello syndrome: involvement of the KRAS gene. J Hum Genet. 2007;52(6):521-6. Epub 2007 Apr 28. PMID:17468812 doi:10.1007/s10038-007-0146-1
↑ Zenker M, Lehmann K, Schulz AL, Barth H, Hansmann D, Koenig R, Korinthenberg R, Kreiss-Nachtsheim M, Meinecke P, Morlot S, Mundlos S, Quante AS, Raskin S, Schnabel D, Wehner LE, Kratz CP, Horn D, Kutsche K. Expansion of the genotypic and phenotypic spectrum in patients with KRAS germline mutations. J Med Genet. 2007 Feb;44(2):131-5. Epub 2006 Oct 20. PMID:17056636 doi:10.1136/jmg.2006.046300
↑ Kratz CP, Zampino G, Kriek M, Kant SG, Leoni C, Pantaleoni F, Oudesluys-Murphy AM, Di Rocco C, Kloska SP, Tartaglia M, Zenker M. Craniosynostosis in patients with Noonan syndrome caused by germline KRAS mutations. Am J Med Genet A. 2009 May;149A(5):1036-40. doi: 10.1002/ajmg.a.32786. PMID:19396835 doi:10.1002/ajmg.a.32786
↑ Gremer L, Merbitz-Zahradnik T, Dvorsky R, Cirstea IC, Kratz CP, Zenker M, Wittinghofer A, Ahmadian MR. Germline KRAS mutations cause aberrant biochemical and physical properties leading to developmental disorders. Hum Mutat. 2011 Jan;32(1):33-43. doi: 10.1002/humu.21377. Epub 2010 Dec 9. PMID:20949621 doi:10.1002/humu.21377
↑ Deng GR, Lu YY, Chen SM, Miao J, Lu GR, Li H, Cai H, Xu XL, E Z, Liu PN. Activated c-Ha-ras oncogene with a guanine to thymine transversion at the twelfth codon in a human stomach cancer cell line. Cancer Res. 1987 Jun 15;47(12):3195-8. PMID:3034404
↑ Lee KH, Lee JS, Suh C, Kim SW, Kim SB, Lee JH, Lee MS, Park MY, Sun HS, Kim SH. Clinicopathologic significance of the K-ras gene codon 12 point mutation in stomach cancer. An analysis of 140 cases. Cancer. 1995 Jun 15;75(12):2794-801. PMID:7773929
↑ Lee SH, Lee JW, Soung YH, Kim HS, Park WS, Kim SY, Lee JH, Park JY, Cho YG, Kim CJ, Nam SW, Kim SH, Lee JY, Yoo NJ. BRAF and KRAS mutations in stomach cancer. Oncogene. 2003 Oct 9;22(44):6942-5. PMID:14534542 doi:10.1038/sj.onc.1206749
↑ Motojima K, Urano T, Nagata Y, Shiku H, Tsurifune T, Kanematsu T. Detection of point mutations in the Kirsten-ras oncogene provides evidence for the multicentricity of pancreatic carcinoma. Ann Surg. 1993 Feb;217(2):138-43. PMID:8439212
↑ Maciag AE, Yang Y, Sharma AK, Turner DM, DeHart CJ, Abdelkarim H, Fan L, Smith BP, Kumari V, Dyba M, Rigby M, Castillo Badillo JA, Adams L, Fornelli L, Fox S, Brafman A, Turbyville T, Gillette W, Messing S, Agamasu C, Wolfe AL, Gysin S, Chan AH, Simanshu DK, Esposito D, Chertov O, Stephen AG, Arkin M, Renslo A, Kelleher NL, Gaponenko V, Lightstone FC, Nissley DV, McCormick F. Blocking C-terminal processing of KRAS4b via a direct covalent attack on the CaaX-box cysteine. Proc Natl Acad Sci U S A. 2025 May 13;122(19):e2410766122. PMID:40343987 doi:10.1073/pnas.2410766122

1 Structural highlights
2 Disease
3 Function
4 Publication Abstract from PubMed
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/7kyz"

Categories: Homo sapiens | Large Structures | Maciag AE | Sharma AK

@@ Line 4: / Line 4: @@
 == Structural highlights ==
 <table><tr><td colspan='2'>[[7kyz]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7KYZ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7KYZ FirstGlance]. <br>
-</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=7kyz FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7kyz OCA], [https://pdbe.org/7kyz PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7kyz RCSB], [https://www.ebi.ac.uk/pdbsum/7kyz PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7kyz ProSAT]</span></td></tr>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Solution NMR, 20 models</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=7kyz FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7kyz OCA], [https://pdbe.org/7kyz PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7kyz RCSB], [https://www.ebi.ac.uk/pdbsum/7kyz PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7kyz ProSAT]</span></td></tr>
 </table>
 == Disease ==
@@ Line 10: / Line 11: @@
 == 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 ==
+RAS is the most frequently mutated oncogene in cancer. RAS proteins show high sequence similarities in their G-domains but are significantly different in their C-terminal hypervariable regions (HVR). These regions interact with the cell membrane via lipid anchors that result from posttranslational modifications (PTM) of cysteine residues. KRAS4b is unique as it has only one cysteine that undergoes PTM, C185. Small molecule covalent modification of C185 would block any form of prenylation and subsequently inhibit attachment of KRAS4b to the cell membrane, blocking its biological activity. We translated this concept to the discovery and development of disulfide tethering screen hits into irreversible covalent modifiers of C185. These compounds inhibited proliferation of KRAS4b-driven mouse embryonic fibroblasts, but not cells driven by N-myristoylated KRAS4b that harbor a C185S mutation and are not dependent on C185 prenylation. Top-down proteomics was used to confirm target engagement in cells. These compounds bind in a pocket formed when the HVR folds back between helix 3 and 4 in the G-domain (HVR-alpha3-alpha4). This interaction can happen in the absence of small molecules as predicted by molecular dynamics simulations and is stabilized in the presence of C185 binders as confirmed by small-angle X-ray scattering and solution NMR. NOESY-HSQC, an NMR approach that measures internuclear distances of 6 A or less, and structure analysis identified the critical residues and interactions that define the HVR-alpha3-alpha4 pocket. Further development of compounds that bind to this pocket could be the basis of a new approach to targeting KRAS cancers.
+Blocking C-terminal processing of KRAS4b via a direct covalent attack on the CaaX-box cysteine.,Maciag AE, Yang Y, Sharma AK, Turner DM, DeHart CJ, Abdelkarim H, Fan L, Smith BP, Kumari V, Dyba M, Rigby M, Castillo Badillo JA, Adams L, Fornelli L, Fox S, Brafman A, Turbyville T, Gillette W, Messing S, Agamasu C, Wolfe AL, Gysin S, Chan AH, Simanshu DK, Esposito D, Chertov O, Stephen AG, Arkin M, Renslo A, Kelleher NL, Gaponenko V, Lightstone FC, Nissley DV, McCormick F Proc Natl Acad Sci U S A. 2025 May 13;122(19):e2410766122. doi: , 10.1073/pnas.2410766122. Epub 2025 May 9. PMID:40343987<ref>PMID:40343987</ref>
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
+</div>
+<div class="pdbe-citations 7kyz" style="background-color:#fffaf0;"></div>
 == References ==
 <references/>

7kyz

From Proteopedia

Current revision

Solution structures of full-length K-RAS bound to GDP

Structural highlights

Disease

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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