7RMA

Structure of the fourth UIM (Ubiquitin Interacting Motif) of ANKRD13D in complex with a high affinity UbV (Ubiquitin Variant)

Summary for 7RMA

• Entry DOI: 10.2210/pdb7rma/pdb
• Related: 6NJG
• Descriptor: Ubiquitin Variant, Ankyrin repeat domain-containing protein 13D, SULFATE ION, ... (5 entities in total)
• Functional Keywords: ubiquitin-interacting motif, uim, ubiquitin variant, protein engineering, protein recognition, strand-exchange dimer, protein binding
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 2
• Total formula weight: 12393.89

Authors

Singer, A.U.,Manczyk, N.,Veggiani, G.,Sicheri, F.,Sidhu, S.S. (deposition date: 2021-07-27, release date: 2022-05-11, Last modification date: 2023-10-18)

Primary citation

Veggiani, G.,Yates, B.P.,Martyn, G.D.,Manczyk, N.,Singer, A.U.,Kurinov, I.,Sicheri, F.,Sidhu, S.S.
Panel of Engineered Ubiquitin Variants Targeting the Family of Human Ubiquitin Interacting Motifs.
Acs Chem.Biol., 17:941-956, 2022

PubMed Abstract: Ubiquitin (Ub)-binding domains embedded in intracellular proteins act as readers of the complex Ub code and contribute to regulation of numerous eukaryotic processes. Ub-interacting motifs (UIMs) are short α-helical modular recognition elements whose role in controlling proteostasis and signal transduction has been poorly investigated. Moreover, impaired or aberrant activity of UIM-containing proteins has been implicated in numerous diseases, but targeting modular recognition elements in proteins remains a major challenge. To overcome this limitation, we developed Ub variants (UbVs) that bind to 42 UIMs in the human proteome with high affinity and specificity. Structural analysis of a UbV:UIM complex revealed the molecular determinants of enhanced affinity and specificity. Furthermore, we showed that a UbV targeting a UIM in the cancer-associated Ub-specific protease 28 potently inhibited catalytic activity. Our work demonstrates the versatility of UbVs to target short α-helical Ub receptors with high affinity and specificity. Moreover, the UbVs provide a toolkit to investigate the role of UIMs in regulating and transducing Ub signals and establish a general strategy for the systematic development of probes for Ub-binding domains.

PubMed: 35385646
DOI: 10.1021/acschembio.2c00089

Experimental method

X-RAY DIFFRACTION (2 Å)