登録情報 データベース : EMDB / ID : EMD-27411 ダウンロードとリンクタイトル Ectodomain of full-length KIT(T417I,delta418-419)-SCF dimers マップデータEctodomain local refinement of KIT(T417I,delta418-419)-SCF dimers 詳細 試料複合体 : Full-length KIT(T417I,delta418-419)-SCF dimers reconstituted in amphipolタンパク質・ペプチド : Isoform 2 of Mast/stem cell growth factor receptor Kitタンパク質・ペプチド : Soluble KIT ligandリガンド : 2-acetamido-2-deoxy-beta-D-glucopyranose 詳細機能・相同性 機能・相同性情報分子機能 ドメイン・相同性 構成要素
positive regulation of myeloid leukocyte differentiation / negative regulation of mast cell apoptotic process / stem cell factor receptor binding / mast cell migration / positive regulation of hematopoietic progenitor cell differentiation / positive regulation of hematopoietic stem cell proliferation / Dasatinib-resistant KIT mutants / Imatinib-resistant KIT mutants / KIT mutants bind TKIs / Masitinib-resistant KIT mutants ... positive regulation of myeloid leukocyte differentiation / negative regulation of mast cell apoptotic process / stem cell factor receptor binding / mast cell migration / positive regulation of hematopoietic progenitor cell differentiation / positive regulation of hematopoietic stem cell proliferation / Dasatinib-resistant KIT mutants / Imatinib-resistant KIT mutants / KIT mutants bind TKIs / Masitinib-resistant KIT mutants / Nilotinib-resistant KIT mutants / Regorafenib-resistant KIT mutants / Signaling by kinase domain mutants of KIT / Sunitinib-resistant KIT mutants / Signaling by juxtamembrane domain KIT mutants / Sorafenib-resistant KIT mutants / Signaling by extracellular domain mutants of KIT / stem cell factor receptor activity / hematopoietic stem cell migration / melanocyte adhesion / positive regulation of pyloric antrum smooth muscle contraction / positive regulation of colon smooth muscle contraction / erythropoietin-mediated signaling pathway / positive regulation of vascular associated smooth muscle cell differentiation / melanocyte migration / positive regulation of dendritic cell cytokine production / myeloid leukocyte differentiation / Kit signaling pathway / positive regulation of melanocyte differentiation / regulation of bile acid metabolic process / positive regulation of small intestine smooth muscle contraction / mast cell apoptotic process / mast cell differentiation / positive regulation of mast cell proliferation / mast cell chemotaxis / Fc receptor signaling pathway / glycosphingolipid metabolic process / mast cell proliferation / positive regulation of long-term neuronal synaptic plasticity / detection of mechanical stimulus involved in sensory perception of sound / positive regulation of pseudopodium assembly / positive regulation of mast cell cytokine production / immature B cell differentiation / melanocyte differentiation / lymphoid progenitor cell differentiation / germ cell migration / myeloid progenitor cell differentiation / digestive tract development / positive regulation of Ras protein signal transduction / negative regulation of programmed cell death / 神経堤 / embryonic hemopoiesis / positive regulation of leukocyte migration / 顔料 / lamellipodium assembly / tongue development / megakaryocyte development / Regulation of KIT signaling / stem cell population maintenance / mast cell degranulation / positive regulation of Notch signaling pathway / cytokine binding / negative regulation of reproductive process / negative regulation of developmental process / growth factor binding / somatic stem cell population maintenance / 造血 / T cell differentiation / spermatid development / ectopic germ cell programmed cell death / hematopoietic progenitor cell differentiation / : / response to cadmium ion / T cell proliferation / positive regulation of T cell proliferation / ovarian follicle development / positive regulation of tyrosine phosphorylation of STAT protein / extrinsic apoptotic signaling pathway in absence of ligand / TFAP2 (AP-2) family regulates transcription of growth factors and their receptors / SH2 domain binding / transmembrane receptor protein tyrosine kinase activity / cell chemotaxis / B cell differentiation / 赤血球形成 / acrosomal vesicle / Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants / epithelial cell proliferation / filopodium / cytokine activity / 細胞分化 / positive regulation of receptor signaling pathway via JAK-STAT / growth factor activity / visual learning / Signaling by SCF-KIT / response to organic cyclic compound / 受容体型チロシンキナーゼ / cytoplasmic side of plasma membrane / 核小体 / cytokine-mediated signaling pathway / positive regulation of DNA-binding transcription factor activity 類似検索 - 分子機能 Stem cell factor / Stem cell factor / Mast/stem cell growth factor receptor / Tyrosine-protein kinase, receptor class III, conserved site / Receptor tyrosine kinase class III signature. / Four-helical cytokine-like, core / 抗体 / 免疫グロブリンフォールド / Immunoglobulin subtype 2 / Immunoglobulin C-2 Type ... Stem cell factor / Stem cell factor / Mast/stem cell growth factor receptor / Tyrosine-protein kinase, receptor class III, conserved site / Receptor tyrosine kinase class III signature. / Four-helical cytokine-like, core / 抗体 / 免疫グロブリンフォールド / Immunoglobulin subtype 2 / Immunoglobulin C-2 Type / Tyrosine-protein kinase, catalytic domain / Tyrosine kinase, catalytic domain / Tyrosine protein kinases specific active-site signature. / Immunoglobulin subtype / 抗体 / Tyrosine-protein kinase, active site / Protein tyrosine and serine/threonine kinase / Serine-threonine/tyrosine-protein kinase, catalytic domain / Ig-like domain profile. / Immunoglobulin-like domain / Immunoglobulin-like domain superfamily / Protein kinase, ATP binding site / Protein kinases ATP-binding region signature. / Immunoglobulin-like fold / Protein kinase domain profile. / Protein kinase domain / Protein kinase-like domain superfamily 類似検索 - ドメイン・相同性 Mast/stem cell growth factor receptor Kit / Kit ligand 類似検索 - 構成要素生物種 Homo sapiens (ヒト)手法 単粒子再構成法 / クライオ電子顕微鏡法 / 解像度 : 3.96 Å 詳細 データ登録者Krimmer SG / Bertoletti N / Mi W / Schlessinger J 資金援助 1件 詳細 詳細を隠すOrganization Grant number 国 Not funded
引用ジャーナル : Proc Natl Acad Sci U S A / 年 : 2023タイトル : Cryo-EM analyses of KIT and oncogenic mutants reveal structural oncogenic plasticity and a target for therapeutic intervention.著者 : Stefan G Krimmer / Nicole Bertoletti / Yoshihisa Suzuki / Luka Katic / Jyotidarsini Mohanty / Sheng Shu / Sangwon Lee / Irit Lax / Wei Mi / Joseph Schlessinger / 要旨 : The receptor tyrosine kinase KIT and its ligand stem cell factor (SCF) are required for the development of hematopoietic stem cells, germ cells, and other cells. A variety of human cancers, such as ... The receptor tyrosine kinase KIT and its ligand stem cell factor (SCF) are required for the development of hematopoietic stem cells, germ cells, and other cells. A variety of human cancers, such as acute myeloid leukemia, gastrointestinal stromal tumor, and mast cell leukemia, are driven by somatic gain-of-function KIT mutations. Here, we report cryo electron microscopy (cryo-EM) structural analyses of full-length wild-type and two oncogenic KIT mutants, which show that the overall symmetric arrangement of the extracellular domain of ligand-occupied KIT dimers contains asymmetric D5 homotypic contacts juxtaposing the plasma membrane. Mutational analysis of KIT reveals in D5 region an "Achilles heel" for therapeutic intervention. A ligand-sensitized oncogenic KIT mutant exhibits a more comprehensive and stable D5 asymmetric conformation. A constitutively active ligand-independent oncogenic KIT mutant adopts a V-shaped conformation solely held by D5-mediated contacts. Binding of SCF to this mutant fully restores the conformation of wild-type KIT dimers, including the formation of salt bridges responsible for D4 homotypic contacts and other hallmarks of SCF-induced KIT dimerization. These experiments reveal an unexpected structural plasticity of oncogenic KIT mutants and a therapeutic target in D5. 履歴 登録 2022年6月22日 - ヘッダ(付随情報) 公開 2023年3月29日 - マップ公開 2023年3月29日 - 更新 2023年4月5日 - 現状 2023年4月5日 処理サイト : RCSB / 状態 : 公開
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