PDBsum entry 4xr8

Viral protein/ antitumor protein

PDB id: 4xr8

Contents

Protein chains

383 a.a.

199 a.a.

143 a.a.

151 a.a.

Ligands

GLC-GLC ×2

PEG ×4

EDO

Metals

_ZN ×6

Waters ×362

PDB id:

4xr8

Name:

Viral protein/ antitumor protein

Title:

Crystal structure of the hpv16 e6/e6ap/p53 ternary complex at 2.25 a resolution

Structure:

Maltose-binding periplasmic protein, ubiquitin ligase e6ap. Chain: a, b. Synonym: mbp,mmbp,maltodextrin-binding protein,mbp,mmbp,maltodextrin- binding protein. Engineered: yes. Mutation: yes. Cellular tumor antigen p53. Chain: c, d. Synonym: antigen ny-co-13,phosphoprotein p53,tumor suppressor p53.

Source:

Escherichia coli, homo sapiens. Human. Organism_taxid: 83333, 9606. Strain: k12. Gene: male, b4034, jw3994. Expressed in: escherichia coli k-12. Expression_system_taxid: 83333. Homo sapiens. Organism_taxid: 9606.

Resolution:

2.25Å R-factor: 0.196 R-free: 0.246

Authors:

D.Martinez-Zapien,F.X.Ruiz,A.Mitschler,A.Podjarny,G.Trave,K.Zanier

Key ref:

D.Martinez-Zapien et al. (2016). Structure of the E6/E6AP/p53 complex required for HPV-mediated degradation of p53. Nature, 529, 541-545. PubMed id: 26789255 DOI: 10.1038/nature16481

Date:

20-Jan-15 Release date: 03-Feb-16

Protein chains

P0AEX9  (MALE_ECOLI) -  Maltose/maltodextrin-binding periplasmic protein from Escherichia coli (strain K12)

Seq: 396 a.a.

Struc: 383 a.a.*

Protein chains

Q05086  (UBE3A_HUMAN) -  Ubiquitin-protein ligase E3A from Homo sapiens

Seq: 875 a.a.

Struc: 383 a.a.*

Protein chains

P04637  (P53_HUMAN) -  Cellular tumor antigen p53 from Homo sapiens

Seq: 393 a.a.

Struc: 199 a.a.

Protein chain

P03126  (VE6_HPV16) -  Protein E6 from Human papillomavirus type 16

Seq: 158 a.a.

Struc: 143 a.a.*

Protein chain

P03126  (VE6_HPV16) -  Protein E6 from Human papillomavirus type 16

Seq: 158 a.a.

Struc: 151 a.a.*

* PDB and UniProt seqs differ at 369 residue positions (black crosses)

Enzyme reactions

• Enzyme class 2: Chains A, B, C, D, F, H: E.C.?
• Enzyme class 3: Chains A, B: E.C.2.3.2.26 - HECT-type E3 ubiquitin transferase.
• Reaction: S-ubiquitinyl-[E2 ubiquitin-conjugating enzyme]-L-cysteine + [acceptor protein]-L-lysine = [E2 ubiquitin-conjugating enzyme]-L-cysteine + N₆- ubiquitinyl-[acceptor protein]-L-lysine

Note, where more than one E.C. class is given (as above), each may correspond to a different protein domain or, in the case of polyprotein precursors, to a different mature protein.

DOI no: 10.1038/nature16481

Nature 529:541-545 (2016)

PubMed id: 26789255

Structure of the E6/E6AP/p53 complex required for HPV-mediated degradation of p53.

D.Martinez-Zapien, F.X.Ruiz, J.Poirson, A.Mitschler, J.Ramirez, A.Forster, A.Cousido-Siah, M.Masson, S.Vande Pol, A.Podjarny, G.Travé, K.Zanier.

ABSTRACT

The p53 pro-apoptotic tumour suppressor is mutated or functionally altered in most cancers. In epithelial tumours induced by 'high-risk' mucosal human papilloma viruses, including human cervical carcinoma and a growing number of head-and-neck cancers, p53 is degraded by the viral oncoprotein E6 (ref. 2). In this process, E6 binds to a short leucine (L)-rich LxxLL consensus sequence within the cellular ubiquitin ligase E6AP. Subsequently, the E6/E6AP heterodimer recruits and degrades p53 (ref. 4). Neither E6 nor E6AP are separately able to recruit p53 (refs 3, 5), and the precise mode of assembly of E6, E6AP and p53 is unknown. Here we solve the crystal structure of a ternary complex comprising full-length human papilloma virus type 16 (HPV-16) E6, the LxxLL motif of E6AP and the core domain of p53. The LxxLL motif of E6AP renders the conformation of E6 competent for interaction with p53 by structuring a p53-binding cleft on E6. Mutagenesis of critical positions at the E6-p53 interface disrupts p53 degradation. The E6-binding site of p53 is distal from previously described DNA- and protein-binding surfaces of the core domain. This suggests that, in principle, E6 may avoid competition with cellular factors by targeting both free and bound p53 molecules. The E6/E6AP/p53 complex represents a prototype of viral hijacking of both the ubiquitin-mediated protein degradation pathway and the p53 tumour suppressor pathway. The present structure provides a framework for the design of inhibitory therapeutic strategies against oncogenesis mediated by human papilloma virus.