7l97

Crystal structure of STAMBPL1 in complex with an engineered binder

spinqualitylabelsall models 7l97, resolution 2.01Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 7l97 is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.01Å Ligands: EDO, SO4, UNX, ZN Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function STALP_HUMAN Zinc metalloprotease that specifically cleaves 'Lys-63'-linked polyubiquitin chains. Does not cleave 'Lys-48'-linked polyubiquitin chains. Publication Abstract from PubMed Ubiquitination is a crucial posttranslational protein modification involved in a myriad of biological pathways. This modification is reversed by deubiquitinases (DUBs) that deconjugate the single ubiquitin (Ub) moiety or poly-Ub chains from substrates. In the past decade, tremendous efforts have been focused on targeting DUBs for drug discovery. However, most chemical compounds with inhibitory activity for DUBs suffer from mild potency and low selectivity. To overcome these obstacles, we developed a phage display-based protein engineering strategy for generating Ub variant (UbV) inhibitors, which was previously successfully applied to the Ub-specific protease (USP) family of cysteine proteases. In this work, we leveraged the UbV platform to selectively target STAMBP, a member of the JAB1/MPN/MOV34 (JAMM) metalloprotease family of DUB enzymes. We identified two UbVs (UbV(SP.1) and UbV(SP.3)) that bind to STAMBP with high affinity but differ in their selectivity for the closely related paralog STAMBPL1. We determined the STAMBPL1-UbV(SP.1) complex structure by X-ray crystallography, revealing hotspots of the JAMM-UbV interaction. Finally, we show that UbV(SP.1) and UbV(SP.3) are potent inhibitors of STAMBP isopeptidase activity, far exceeding the reported small-molecule inhibitor BC-1471. This work demonstrates that UbV technology is suitable to develop molecules as tools to target metalloproteases, which can be used to further understand the cellular function of JAMM family DUBs. Structural and functional characterization of ubiquitin variant inhibitors for the JAMM-family deubiquitinases STAMBP and STAMBPL1.,Guo Y, Liu Q, Mallette E, Caba C, Hou F, Fux J, LaPlante G, Dong A, Zhang Q, Zheng H, Tong Y, Zhang W J Biol Chem. 2021 Oct;297(4):101107. doi: 10.1016/j.jbc.2021.101107. Epub 2021 , Aug 21. PMID:34425109 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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