- EMDB-42151: Structure of the P1B7 antibody bound to the Sotorasib-modified KR... -
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基本情報
登録情報
データベース: EMDB / ID: EMD-42151
タイトル
Structure of the P1B7 antibody bound to the Sotorasib-modified KRas G12C peptide presented by the A*03:01 MHC I complex
マップデータ
試料
複合体: P1B7 antibody:V7-Sotorasib A*03:01 MHC I complex
タンパク質・ペプチド: HLA class I histocompatibility antigen, A alpha chain
タンパク質・ペプチド: Beta-2-microglobulin
タンパク質・ペプチド: P1B7 Heavy Chain
タンパク質・ペプチド: P1B7 Light Chain
タンパク質・ペプチド: GTPase KRas, N-terminally processed
リガンド: AMG 510 (bound form)
キーワード
antibody / MHC / haptenated peptide / PEPTIDE BINDING PROTEIN / IMMUNE SYSTEM
機能・相同性
機能・相同性情報
forebrain astrocyte development / positive regulation of memory T cell activation / T cell mediated cytotoxicity directed against tumor cell target / TAP complex binding / Golgi medial cisterna / positive regulation of CD8-positive, alpha-beta T cell activation / CD8-positive, alpha-beta T cell activation / positive regulation of CD8-positive, alpha-beta T cell proliferation / negative regulation of epithelial cell differentiation / type I pneumocyte differentiation ...forebrain astrocyte development / positive regulation of memory T cell activation / T cell mediated cytotoxicity directed against tumor cell target / TAP complex binding / Golgi medial cisterna / positive regulation of CD8-positive, alpha-beta T cell activation / CD8-positive, alpha-beta T cell activation / positive regulation of CD8-positive, alpha-beta T cell proliferation / negative regulation of epithelial cell differentiation / type I pneumocyte differentiation / regulation of synaptic transmission, GABAergic / epithelial tube branching involved in lung morphogenesis / CD8 receptor binding / Rac protein signal transduction / antigen processing and presentation of exogenous peptide antigen via MHC class I / beta-2-microglobulin binding / positive regulation of Rac protein signal transduction / endoplasmic reticulum exit site / Signaling by RAS GAP mutants / Signaling by RAS GTPase mutants / Activation of RAS in B cells / antigen processing and presentation of endogenous peptide antigen via MHC class I via ER pathway, TAP-dependent / skeletal muscle cell differentiation / TAP binding / RAS signaling downstream of NF1 loss-of-function variants / protection from natural killer cell mediated cytotoxicity / RUNX3 regulates p14-ARF / SOS-mediated signalling / Activated NTRK3 signals through RAS / Activated NTRK2 signals through RAS / antigen processing and presentation of endogenous peptide antigen via MHC class I via ER pathway, TAP-independent / SHC1 events in ERBB4 signaling / antigen processing and presentation of endogenous peptide antigen via MHC class Ib / Signalling to RAS / Activated NTRK2 signals through FRS2 and FRS3 / SHC-related events triggered by IGF1R / Estrogen-stimulated signaling through PRKCZ / glial cell proliferation / SHC-mediated cascade:FGFR3 / detection of bacterium / MET activates RAS signaling / SHC-mediated cascade:FGFR2 / Signaling by PDGFRA transmembrane, juxtamembrane and kinase domain mutants / Signaling by PDGFRA extracellular domain mutants / PTK6 Regulates RHO GTPases, RAS GTPase and MAP kinases / SHC-mediated cascade:FGFR4 / Signaling by FGFR4 in disease / Erythropoietin activates RAS / SHC-mediated cascade:FGFR1 / T cell receptor binding / FRS-mediated FGFR3 signaling / Signaling by CSF3 (G-CSF) / Signaling by FLT3 ITD and TKD mutants / protein-membrane adaptor activity / FRS-mediated FGFR2 signaling / FRS-mediated FGFR4 signaling / Signaling by FGFR3 in disease / p38MAPK events / FRS-mediated FGFR1 signaling / Tie2 Signaling / positive regulation of glial cell proliferation / Signaling by FGFR2 in disease / striated muscle cell differentiation / GRB2 events in EGFR signaling / SHC1 events in EGFR signaling / homeostasis of number of cells within a tissue / Signaling by FLT3 fusion proteins / FLT3 Signaling / Signaling by FGFR1 in disease / EGFR Transactivation by Gastrin / NCAM signaling for neurite out-growth / CD209 (DC-SIGN) signaling / GRB2 events in ERBB2 signaling / Downstream signal transduction / Ras activation upon Ca2+ influx through NMDA receptor / SHC1 events in ERBB2 signaling / Insulin receptor signalling cascade / Constitutive Signaling by Overexpressed ERBB2 / : / : / Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants / positive regulation of receptor binding / early endosome lumen / Nef mediated downregulation of MHC class I complex cell surface expression / negative regulation of receptor binding / DAP12 interactions / VEGFR2 mediated cell proliferation / small monomeric GTPase / cellular response to iron ion / lumenal side of endoplasmic reticulum membrane / Endosomal/Vacuolar pathway / Antigen Presentation: Folding, assembly and peptide loading of class I MHC / FCERI mediated MAPK activation / peptide antigen assembly with MHC class II protein complex / antigen processing and presentation of exogenous protein antigen via MHC class Ib, TAP-dependent / cellular response to iron(III) ion / MHC class II protein complex / negative regulation of forebrain neuron differentiation / RAF activation / Signaling by ERBB2 TMD/JMD mutants 類似検索 - 分子機能
Small GTPase, Ras-type / Small GTPase Ras domain profile. / Ran (Ras-related nuclear proteins) /TC4 subfamily of small GTPases / MHC class I, alpha chain, C-terminal / MHC_I C-terminus / MHC class I alpha chain, alpha1 alpha2 domains / Rho (Ras homology) subfamily of Ras-like small GTPases / Class I Histocompatibility antigen, domains alpha 1 and 2 / Ras subfamily of RAS small GTPases / Small GTPase ...Small GTPase, Ras-type / Small GTPase Ras domain profile. / Ran (Ras-related nuclear proteins) /TC4 subfamily of small GTPases / MHC class I, alpha chain, C-terminal / MHC_I C-terminus / MHC class I alpha chain, alpha1 alpha2 domains / Rho (Ras homology) subfamily of Ras-like small GTPases / Class I Histocompatibility antigen, domains alpha 1 and 2 / Ras subfamily of RAS small GTPases / Small GTPase / Ras family / Beta-2-Microglobulin / : / MHC class I-like antigen recognition-like / MHC class I-like antigen recognition-like superfamily / Rab subfamily of small GTPases / MHC classes I/II-like antigen recognition protein / : / Small GTP-binding protein domain / Immunoglobulin/major histocompatibility complex, conserved site / Immunoglobulins and major histocompatibility complex proteins signature. / Immunoglobulin C-Type / Immunoglobulin C1-set / Immunoglobulin C1-set domain / Ig-like domain profile. / Immunoglobulin-like domain / Immunoglobulin-like domain superfamily / Immunoglobulin-like fold / P-loop containing nucleoside triphosphate hydrolase 類似検索 - ドメイン・相同性
GTPase KRas / HLA class I histocompatibility antigen, A alpha chain / Beta-2-microglobulin 類似検索 - 構成要素
National Institutes of Health/National Cancer Institute (NIH/NCI)
P41-GM103393
米国
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)
T32 GM 064337
米国
Howard Hughes Medical Institute (HHMI)
米国
引用
ジャーナル: Cancer Res / 年: 2025 タイトル: Therapeutic Targeting and Structural Characterization of a Sotorasib-Modified KRAS G12C-MHC I Complex Demonstrate the Antitumor Efficacy of Hapten-Based Strategies. 著者: Apurva Pandey / Peter J Rohweder / Lieza M Chan / Chayanid Ongpipattanakul / Dong Hee Chung / Bryce Paolella / Fiona M Quimby / Ngoc Nguyen / Kliment A Verba / Michael J Evans / Charles S Craik / 要旨: Antibody-based therapies have emerged as a powerful strategy for the management of diverse cancers. Unfortunately, tumor-specific antigens remain challenging to identify and target. Recent work ...Antibody-based therapies have emerged as a powerful strategy for the management of diverse cancers. Unfortunately, tumor-specific antigens remain challenging to identify and target. Recent work established that inhibitor-modified peptide adducts derived from KRAS G12C are competent for antigen presentation via MHC I and can be targeted by antibody-based therapeutics, offering a means to directly target an intracellular oncoprotein at the cell surface with combination therapies. Here, we validated the antigen display of "haptenated" KRAS G12C peptide fragments on tumors in mouse models treated with the FDA-approved KRAS G12C covalent inhibitor sotorasib using PET/CT imaging of an 89Zr-labeled P1B7 IgG antibody, which selectively binds sotorasib-modified KRAS G12C-MHC I complexes. Targeting this peptide-MHC I complex with radioligand therapy using 225Ac- or 177Lu-P1B7 IgG effectively inhibited tumor growth in combination with sotorasib. Elucidation of the 3.1 Å cryo-EM structure of P1B7 bound to a haptenated KRAS G12C peptide-MHC I complex confirmed that the sotorasib-modified KRAS G12C peptide is presented via a canonical binding pose and showed that P1B7 binds the complex in a T-cell receptor-like manner. Together, these findings demonstrate the potential value of targeting unique oncoprotein-derived, haptenated MHC I complexes with radioligand therapeutics and provide a structural framework for developing next generation antibodies. Significance: Radioligand therapy using an antibody targeting KRAS-derived, sotorasib-modified MHC I complexes elicits antitumor effects superior to those of sotorasib alone and provides a potential strategy to repurpose sotorasib as a hapten to overcome resistance.