6ziz

From Proteopedia

CRYSTAL STRUCTURE OF NRAS Q61R IN COMPLEX WITH GTP AND COMPOUND 18

Structural highlights

6ziz is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 1.785Å
Ligands:	, ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

RASN_HUMAN Defects in NRAS 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. Defects in NRAS are the cause of Noonan syndrome type 6 (NS6) [MIM:613224. A syndrome characterized by facial dysmorphic features such as hypertelorism, a downward eyeslant and low-set posteriorly rotated ears. Other features can include short stature, a short neck with webbing or redundancy of skin, cardiac anomalies, deafness, motor delay and variable intellectual deficits.^[1] Defects in NRAS are the cause of autoimmune lymphoproliferative syndrome type 4 (ALPS4) [MIM:614470. A disorder of apoptosis, characterized by chronic accumulation of non-malignant lymphocytes, defective lymphocyte apoptosis, and an increased risk for the development of hematologic malignancies.^[2]

Function

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

Publication Abstract from PubMed

Activating mutations in the three human RAS genes, KRAS, NRAS and HRAS, are among the most common oncogenic drivers in human cancers. Covalent KRAS(G12C) inhibitors, which bind to the switch II pocket in the 'off state' of KRAS, represent the first direct KRAS drugs that entered human clinical trials. However, the remaining 85% of non-KRAS(G12C)-driven cancers remain undrugged as do NRAS and HRAS and no drugs targeting the 'on state' have been discovered so far. The switch I/II pocket is a second pocket for which the nanomolar inhibitor BI-2852 has been discovered. Here, we elucidate inhibitor binding modes in KRAS, NRAS and HRAS on and off and discuss future strategies to drug all RAS isoforms with this one pocket.

Drugging all RAS isoforms with one pocket.,Kessler D, Bergner A, Bottcher J, Fischer G, Dobel S, Hinkel M, Mullauer B, Weiss-Puxbaum A, McConnell DB Future Med Chem. 2020 Aug 11. doi: 10.4155/fmc-2020-0221. PMID:32779487^[3]

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

References

↑ Cirstea IC, Kutsche K, Dvorsky R, Gremer L, Carta C, Horn D, Roberts AE, Lepri F, Merbitz-Zahradnik T, Konig R, Kratz CP, Pantaleoni F, Dentici ML, Joshi VA, Kucherlapati RS, Mazzanti L, Mundlos S, Patton MA, Silengo MC, Rossi C, Zampino G, Digilio C, Stuppia L, Seemanova E, Pennacchio LA, Gelb BD, Dallapiccola B, Wittinghofer A, Ahmadian MR, Tartaglia M, Zenker M. A restricted spectrum of NRAS mutations causes Noonan syndrome. Nat Genet. 2010 Jan;42(1):27-9. Epub 2009 Dec 6. PMID:19966803 doi:10.1038/ng.497
↑ Oliveira JB, Bidere N, Niemela JE, Zheng L, Sakai K, Nix CP, Danner RL, Barb J, Munson PJ, Puck JM, Dale J, Straus SE, Fleisher TA, Lenardo MJ. NRAS mutation causes a human autoimmune lymphoproliferative syndrome. Proc Natl Acad Sci U S A. 2007 May 22;104(21):8953-8. Epub 2007 May 16. PMID:17517660 doi:10.1073/pnas.0702975104
↑ Kessler D, Bergner A, Bottcher J, Fischer G, Dobel S, Hinkel M, Mullauer B, Weiss-Puxbaum A, McConnell DB. Drugging all RAS isoforms with one pocket. Future Med Chem. 2020 Aug 11. doi: 10.4155/fmc-2020-0221. PMID:32779487 doi:http://dx.doi.org/10.4155/fmc-2020-0221