9l6f

From Proteopedia

(Difference between revisions)
Jump to: navigation, search
m (Protected "9l6f" [edit=sysop:move=sysop])
Current revision (10:37, 3 September 2025) (edit) (undo)
 
Line 1: Line 1:
-
'''Unreleased structure'''
 
-
The entry 9l6f is ON HOLD until Paper Publication
+
==Crystal structure of KRas G12D (GDP) in complex with ASP3082==
 +
<StructureSection load='9l6f' size='340' side='right'caption='[[9l6f]], [[Resolution|resolution]] 3.18&Aring;' scene=''>
 +
== Structural highlights ==
 +
<table><tr><td colspan='2'>[[9l6f]] is a 16 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=9L6F OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=9L6F 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]] 3.18&#8491;</td></tr>
 +
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=A1L66:(2~{S},4~{R})-1-[(2~{S})-2-[4-[4-[[6-cyclopropyl-4-[(1~{S},4~{S})-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoranyl-5-methyl-1~{H}-indazol-4-yl)-2-(oxan-4-yloxy)quinazolin-8-yl]oxymethyl]phenyl]-1,2,3-triazol-1-yl]-3-methyl-butanoyl]-~{N}-[(1~{R})-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]-2-oxidanyl-ethyl]-4-oxidanyl-pyrrolidine-2-carboxamide'>A1L66</scene>, <scene name='pdbligand=GDP:GUANOSINE-5-DIPHOSPHATE'>GDP</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</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=9l6f FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=9l6f OCA], [https://pdbe.org/9l6f PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=9l6f RCSB], [https://www.ebi.ac.uk/pdbsum/9l6f PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=9l6f ProSAT]</span></td></tr>
 +
</table>
 +
== Disease ==
 +
[https://www.uniprot.org/uniprot/VHL_HUMAN VHL_HUMAN] Defects in VHL are a cause of susceptibility to pheochromocytoma (PCC) [MIM:[https://omim.org/entry/171300 171300]. A catecholamine-producing tumor of chromaffin tissue of the adrenal medulla or sympathetic paraganglia. The cardinal symptom, reflecting the increased secretion of epinephrine and norepinephrine, is hypertension, which may be persistent or intermittent. Defects in VHL are the cause of von Hippel-Lindau disease (VHLD) [MIM:[https://omim.org/entry/193300 193300]. VHLD is a dominantly inherited familial cancer syndrome characterized by the development of retinal angiomatosis, cerebellar and spinal hemangioblastoma, renal cell carcinoma (RCC), phaeochromocytoma and pancreatic tumors. VHL type 1 is without pheochromocytoma, type 2 is with pheochromocytoma. VHL type 2 is further subdivided into types 2A (pheochromocytoma, retinal angioma, and hemangioblastomas without renal cell carcinoma and pancreatic cyst) and 2B (pheochromocytoma, retinal angioma, and hemangioblastomas with renal cell carcinoma and pancreatic cyst). VHL type 2C refers to patients with isolated pheochromocytoma without hemangioblastoma or renal cell carcinoma. The estimated incidence is 3/100000 births per year and penetrance is 97% by age 60 years.<ref>PMID:10635329</ref> <ref>PMID:8493574</ref> <ref>PMID:7987306</ref> <ref>PMID:7728151</ref> <ref>PMID:8634692</ref> <ref>PMID:8592333</ref> <ref>PMID:8825918</ref> <ref>PMID:8730290</ref> <ref>PMID:8956040</ref> <ref>PMID:9452032</ref> <ref>PMID:9452106</ref> <ref>PMID:10627136</ref> <ref>PMID:9829911</ref> <ref>PMID:9829912</ref> [:]<ref>PMID:10533030</ref> <ref>PMID:10408776</ref> <ref>PMID:16502427</ref> Defects in VHL are the cause of familial erythrocytosis type 2 (ECYT2) [MIM:[https://omim.org/entry/263400 263400]; also called VHL-dependent polycythemia or Chuvash type polycythemia. ECYT2 is an autosomal recessive disorder characterized by an increase in serum red blood cell mass, hypersensitivity of erythroid progenitors to erythropoietin, increased erythropoietin serum levels, and normal oxygen affinity. Patients with ECYT2 carry a high risk for peripheral thrombosis and cerebrovascular events.<ref>PMID:12844285</ref> <ref>PMID:12393546</ref> Defects in VHL are a cause of renal cell carcinoma (RCC) [MIM:[https://omim.org/entry/144700 144700]. Renal cell carcinoma is a heterogeneous group of sporadic or hereditary carcinoma derived from cells of the proximal renal tubular epithelium. It is subclassified into clear cell renal carcinoma (non-papillary carcinoma), papillary renal cell carcinoma, chromophobe renal cell carcinoma, collecting duct carcinoma with medullary carcinoma of the kidney, and unclassified renal cell carcinoma.<ref>PMID:11986208</ref>
 +
== Function ==
 +
[https://www.uniprot.org/uniprot/VHL_HUMAN VHL_HUMAN] Involved in the ubiquitination and subsequent proteasomal degradation via the von Hippel-Lindau ubiquitination complex. Seems to act as target recruitment subunit in the E3 ubiquitin ligase complex and recruits hydroxylated hypoxia-inducible factor (HIF) under normoxic conditions. Involved in transcriptional repression through interaction with HIF1A, HIF1AN and histone deacetylases. Ubiquitinates, in an oxygen-responsive manner, ADRB2.<ref>PMID:9751722</ref> <ref>PMID:10944113</ref> <ref>PMID:19584355</ref>
 +
<div style="background-color:#fffaf0;">
 +
== Publication Abstract from PubMed ==
 +
Kirsten rat sarcoma viral oncogene homolog (KRAS) is one of the most frequently mutated oncogenes in multiple cancers. Multiple types of KRAS mutation are observed in various patients with cancer, and the KRAS(G12D) mutation is the most common. Although multiple covalent inhibitors of the KRAS(G12C) mutation have been identified and clinically validated to date, no drugs have been approved yet for other mutations, including G12D. Herein, we report the discovery and characterization of ASP3082, a KRAS(G12D)-selective degrader, and the crystal structure of the drug-induced ternary complex of KRAS(G12D)/ASP3082/VHL (von Hippel-Lindau). We have also demonstrated an efficient structure-based rational optimization approach, which could be applicable for the optimization of other bifunctional proximity-inducing drugs. ASP3082 effectively induces KRAS(G12D) protein degradation with remarkable selectivity, demonstrates highly efficacious and durable pharmacological activity, and induces tumor regression in multiple KRAS(G12D)-mutated cancer xenograft models. Our results suggest that ASP3082 is a potential therapeutic agent for KRAS(G12D)-mutated cancer, and is now under clinical investigation.
-
Authors: Amano, Y., Tateishi, Y.
+
Discovery of KRAS(G12D) selective degrader ASP3082.,Yoshinari T, Nagashima T, Ishioka H, Inamura K, Nishizono Y, Tasaki M, Iguchi K, Suzuki A, Sato C, Nakayama A, Amano Y, Tateishi Y, Yamanaka Y, Osaki F, Yoshino M, Kuramoto K, Imaizumi T, Hayakawa M Commun Chem. 2025 Aug 23;8(1):254. doi: 10.1038/s42004-025-01662-4. PMID:40849515<ref>PMID:40849515</ref>
-
Description: Crystal structure of KRas G12D (GDP) in complex with ASP3082
+
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-
[[Category: Unreleased Structures]]
+
</div>
-
[[Category: Amano, Y]]
+
<div class="pdbe-citations 9l6f" style="background-color:#fffaf0;"></div>
-
[[Category: Tateishi, Y]]
+
== References ==
 +
<references/>
 +
__TOC__
 +
</StructureSection>
 +
[[Category: Homo sapiens]]
 +
[[Category: Large Structures]]
 +
[[Category: Amano Y]]
 +
[[Category: Tateishi Y]]

Current revision

Crystal structure of KRas G12D (GDP) in complex with ASP3082

PDB ID 9l6f

Drag the structure with the mouse to rotate

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/9l6f"
Personal tools