View source for 9glx


==NRas-Q61R-GTP in complex with the peptide MPB3==
<StructureSection load='9glx' size='340' side='right'caption='[[9glx]], [[Resolution|resolution]] 1.85&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[9glx]] is a 16 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [https://en.wikipedia.org/wiki/Synthetic_construct Synthetic construct]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=9GLX OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=9GLX 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]] 1.85&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CCS:CARBOXYMETHYLATED+CYSTEINE'>CCS</scene>, <scene name='pdbligand=GTP:GUANOSINE-5-TRIPHOSPHATE'>GTP</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=NH2:AMINO+GROUP'>NH2</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=9glx FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=9glx OCA], [https://pdbe.org/9glx PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=9glx RCSB], [https://www.ebi.ac.uk/pdbsum/9glx PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=9glx ProSAT]</span></td></tr>
</table>
== Disease ==
[https://www.uniprot.org/uniprot/RASN_HUMAN RASN_HUMAN] Defects in NRAS 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.  Defects in NRAS are the cause of Noonan syndrome type 6 (NS6) [MIM:[https://omim.org/entry/613224 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.<ref>PMID:19966803</ref>   Defects in NRAS are the cause of autoimmune lymphoproliferative syndrome type 4 (ALPS4) [MIM:[https://omim.org/entry/614470 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.<ref>PMID:17517660</ref> 
== Function ==
[https://www.uniprot.org/uniprot/RASN_HUMAN RASN_HUMAN] Ras proteins bind GDP/GTP and possess intrinsic GTPase activity.
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
RAS proteins control cell proliferation and activating mutations are collectively the most frequent oncogenic event observed in cancer patients, justifying investments into multiple drug discovery efforts. While RAS-directed therapeutic agents targeting either the inactive GDP-bound or the active GTP-bound state have entered the clinic, invariably resistance is observed. Mutations at drug binding sites represent a common resistance mechanism indicating the need to discover new targetable pockets in RAS. Such efforts are hindered by the small globular size of the protein, for long considered undruggable. Here we perform macrocyclic peptides mRNA and nanobody yeast display screens and discover a targetable ligand-induced pocket in RAS. In vitro and cellular experiments with the KM12 and KM12-AM nanobodies show RAS inhibition via displacement of cRAF, by affecting their protein-protein interaction via the less studied cRAF CRD domain. Further, we provide orthogonal functional validation for the discovered binding pocket via mutagenesis experiments. Notably, the discovered RAS-targeting approach enables simultaneous targeting of both GTP-bound active and GDP-bound inactive states and leaves the SwII pocket unaltered, opening possibilities of combinatorial approaches with clinically approved SwII pocket inhibitors.

Identification and characterization of binders to a cryptic and functional pocket in KRAS.,Beyer KS, Klein J, Katz S, Welker P, Lanter M, Guthy D, Pollehn K, Gluck-Gade A, Bleu M, Desogus J, Hattenberger M, Borrello D, Abdul Rahman W, Zink F, Ostermann N, Jahnke W, Dumelin CE, Leder L, Esser O, Muller L, Marzinzik A, Cebe R, Muller K, Galli GG, Tordella L, Cotesta S, Brachmann SM, Maira SM Nat Commun. 2025 Dec 2;16(1):10836. doi: 10.1038/s41467-025-65844-3. PMID:41330964<ref>PMID:41330964</ref>

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