7sjq | pdb_00007sjq

Ex silico engineering of cystine-dense peptides yielding a potent bispecific T-cell engager

spinqualitylabelsall models 7sjq, resolution 2.00Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 7sjq is a 2 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 2Å Ligands: GOL, NA, NAG, SO4 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function PD1L1_HUMAN Involved in the costimulatory signal, essential for T-cell proliferation and production of IL10 and IFNG, in an IL2-dependent and a PDCD1-independent manner. Interaction with PDCD1 inhibits T-cell proliferation and cytokine production. Publication Abstract from PubMed Cystine-dense peptides (CDPs) are a miniprotein class that can drug difficult targets with high affinity and low immunogenicity. Tools for their design, however, are not as developed as those for small-molecule and antibody drugs. CDPs have diverse taxonomic origins, but structural characterization is lacking. Here, we adapted Iterative Threading ASSEmbly Refinement (I-TASSER) and Rosetta protein modeling software for structural prediction of 4298 CDP scaffolds and performed in silico prescreening for CDP binders to targets of interest. Mammalian display screening of a library of docking-enriched, methionine and tyrosine scanned (DEMYS) CDPs against PD-L1 yielded binders from four distinct CDP scaffolds. One was affinity-matured, and cocrystallography yielded a high-affinity (KD = 202 pM) PD-L1-binding CDP that competes with PD-1 for PD-L1 binding. Its subsequent incorporation into a CD3-binding bispecific T cell engager produced a molecule with pM-range in vitro T cell killing potency and which substantially extends survival in two different xenograft tumor-bearing mouse models. Both in vitro and in vivo, the CDP-incorporating bispecific molecule outperformed a comparator antibody-based molecule. This CDP modeling and DEMYS technique can accelerate CDP therapeutic development. Ex silico engineering of cystine-dense peptides yielding a potent bispecific T cell engager.,Crook ZR, Girard EJ, Sevilla GP, Brusniak MY, Rupert PB, Friend DJ, Gewe MM, Clarke M, Lin I, Ruff R, Pakiam F, Phi TD, Bandaranayake A, Correnti CE, Mhyre AJ, Nairn NW, Strong RK, Olson JM Sci Transl Med. 2022 May 18;14(645):eabn0402. doi: 10.1126/scitranslmed.abn0402. , Epub 2022 May 18. PMID:35584229 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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