6GY5

Crystal structure of the kelch domain of human KLHL20 in complex with DAPK1 peptide

Summary for 6GY5

• Entry DOI: 10.2210/pdb6gy5/pdb
• Descriptor: Kelch-like protein 20, Death-associated protein kinase 1, CHLORIDE ION, ... (6 entities in total)
• Functional Keywords: complex, e3 ligase, substrate, ubiquitination, kelch domain, death domain, ligase
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 2
• Total formula weight: 35274.69

Authors

Chen, Z.,Hozjan, V.,Strain-Damerell, C.,Williams, E.,Wang, D.,Cooper, C.D.O.,Sanvitale, C.E.,Fairhead, M.,Carpenter, E.P.,Pike, A.C.W.,Krojer, T.,Srikannathasan, V.,Sorrell, F.,Johansson, C.,Mathea, S.,Burgess-Brown, N.,von Delft, F.,Arrowsmith, C.H.,Edwards, A.M.,Bountra, C.,Bullock, A.N. (deposition date: 2018-06-28, release date: 2018-08-08, Last modification date: 2024-01-17)

Primary citation

Chen, Z.,Picaud, S.,Filippakopoulos, P.,D'Angiolella, V.,Bullock, A.N.
Structural Basis for Recruitment of DAPK1 to the KLHL20 E3 Ligase.
Structure, 27:1395-1404.e4, 2019

PubMed Abstract: BTB-Kelch proteins form the largest subfamily of Cullin-RING E3 ligases, yet their substrate complexes are mapped and structurally characterized only for KEAP1 and KLHL3. KLHL20 is a related CUL3-dependent ubiquitin ligase linked to autophagy, cancer, and Alzheimer's disease that promotes the ubiquitination and degradation of substrates including DAPK1, PML, and ULK1. We identified an "LPDLV"-containing motif in the DAPK1 death domain that determines its recruitment and degradation by KLHL20. A 1.1-Å crystal structure of a KLHL20 Kelch domain-DAPK1 peptide complex reveals DAPK1 binding as a loose helical turn that inserts deeply into the central pocket of the Kelch domain to contact all six blades of the β propeller. Here, KLHL20 forms salt-bridge and hydrophobic interactions including tryptophan and cysteine residues ideally positioned for covalent inhibitor development. The structure highlights the diverse binding modes of β-propeller domains versus linear grooves and suggests a new target for structure-based drug design.

PubMed: 31279627
DOI: 10.1016/j.str.2019.06.005

Experimental method

X-RAY DIFFRACTION (1.086 Å)