9h71

KIT123-KITbp complex (Domains D1-3 of the human receptor tyrosine kinase KIT complexed with the de novo designed minibinder KITbp)

spinqualitylabelsall models 9h71, resolution 2.80Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 9h71 is a 4 chain structure with sequence from Homo sapiens and Synthetic construct. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.8Å Ligands: EDO, GOL, NAG, PEG Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease KIT_HUMAN Defects in KIT are a cause of piebald trait (PBT) [MIM:172800; also known as piebaldism. PBT is an autosomal dominant genetic developmental abnormality of pigmentation characterized by congenital patches of white skin and hair that lack melanocytes. Defects in KIT are a cause of gastrointestinal stromal tumor (GIST) [MIM:606764. Defects in KIT have been associated with testicular germ cell tumor (TGCT) [MIM:273300. A common solid malignancy in males. Germ cell tumors of the testis constitute 95% of all testicular neoplasms. Defects in KIT are a cause of acute myelogenous leukemia (AML) [MIM:601626. AML is a malignant disease in which hematopoietic precursors are arrested in an early stage of development. Note=Somatic mutations that lead to constitutive activation of KIT are detected in AML patients. These mutations fall into two classes, the most common being in-frame internal tandem duplications of variable length in the juxtamembrane region that disrupt the normal regulation of the kinase activity. Likewise, point mutations in the kinase domain can result in a constitutively activated kinase. Function KIT_HUMAN Tyrosine-protein kinase that acts as cell-surface receptor for the cytokine KITLG/SCF and plays an essential role in the regulation of cell survival and proliferation, hematopoiesis, stem cell maintenance, gametogenesis, mast cell development, migration and function, and in melanogenesis. In response to KITLG/SCF binding, KIT can activate several signaling pathways. Phosphorylates PIK3R1, PLCG1, SH2B2/APS and CBL. Activates the AKT1 signaling pathway by phosphorylation of PIK3R1, the regulatory subunit of phosphatidylinositol 3-kinase. Activated KIT also transmits signals via GRB2 and activation of RAS, RAF1 and the MAP kinases MAPK1/ERK2 and/or MAPK3/ERK1. Promotes activation of STAT family members STAT1, STAT3, STAT5A and STAT5B. Activation of PLCG1 leads to the production of the cellular signaling molecules diacylglycerol and inositol 1,4,5-trisphosphate. KIT signaling is modulated by protein phosphatases, and by rapid internalization and degradation of the receptor. Activated KIT promotes phosphorylation of the protein phosphatases PTPN6/SHP-1 and PTPRU, and of the transcription factors STAT1, STAT3, STAT5A and STAT5B. Promotes phosphorylation of PIK3R1, CBL, CRK (isoform Crk-II), LYN, MAPK1/ERK2 and/or MAPK3/ERK1, PLCG1, SRC and SHC1. Publication Abstract from PubMed Designing proteins that bind with high affinity to hydrophilic protein target sites remains a challenging problem. Here we show that RFdiffusion can be conditioned to generate protein scaffolds that form geometrically matched extended beta-sheets with target protein edge beta-strands in which polar groups on the target are complemented with hydrogen bonding groups on the design. We use this approach to design binders against edge-strand target sites on KIT, PDGFRa, ALK-2, ALK-3, FCRL5, NRP1, and alpha-CTX, and obtain higher (pM to mid nM) affinities and success rates than unconditioned RFdiffusion. Despite sharing beta-strand interactions, designs have high specificity, reflecting the precise customization of interacting beta-strand geometry and additional designed binder-target interactions. A binder-KIT co-crystal structure is nearly identical to the design model, confirming the accuracy of the design approach. The ability to robustly generate binders to the hydrophilic interaction surfaces of exposed beta-strands considerably increases the range of computational binder design. Improved protein binder design using beta-pairing targeted RFdiffusion.,Sappington I, Toul M, Lee DS, Robinson SA, Goreshnik I, McCurdy C, Chan TC, Buchholz N, Huang B, Vafeados D, Garcia-Sanchez M, Roullier N, Glogl M, Kim CJ, Watson JL, Torres SV, Verschueren KHG, Verstraete K, Hinck CS, Benard-Valle M, Coventry B, Sims JN, Ahn G, Wang X, Hinck AP, Jenkins TP, Ruohola-Baker H, Banik SM, Savvides SN, Baker D Nat Commun. 2026 Jan 10;17(1):1101. doi: 10.1038/s41467-025-67866-3. PMID:41519838 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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