PDBsum entry 4zgy

Lyase/lyase inhibitor

PDB id: 4zgy

Contents

Protein chains

383 a.a.

125 a.a.

Ligands

PLP

Metals

_MG

Waters ×13

PDB id:

4zgy

Name:

Lyase/lyase inhibitor

Title:

Structure of human ornithine decarboxylase in complex with a c- terminal fragment of antizyme

Structure:

Ornithine decarboxylase. Chain: a. Fragment: unp residues 2-421. Synonym: odc. Engineered: yes. Ornithine decarboxylase antizyme 1. Chain: b. Fragment: unp residues 95-219. Synonym: odc-az.

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: odc1. Expressed in: escherichia coli. Expression_system_taxid: 469008. Gene: oaz1, oaz.

Resolution:

2.63Å R-factor: 0.208 R-free: 0.256

Authors:

H.Y.Wu,N.L.Chan

Key ref:

H.Y.Wu et al. (2015). Structural basis of antizyme-mediated regulation of polyamine homeostasis. Proc Natl Acad Sci U S A, 112, 11229-11234. PubMed id: 26305948 DOI: 10.1073/pnas.1508187112

Date:

24-Apr-15 Release date: 02-Sep-15

Protein chain

P11926  (DCOR_HUMAN) -  Ornithine decarboxylase from Homo sapiens

Seq: 461 a.a.

Struc: 383 a.a.

Protein chain

P54368  (OAZ1_HUMAN) -  Ornithine decarboxylase antizyme 1 from Homo sapiens

Seq: 228 a.a.

Struc: 125 a.a.

Enzyme reactions

• Enzyme class: Chain A: E.C.4.1.1.17 - ornithine decarboxylase.
• Pathway: Spermine Biosynthesis
• Reaction: L-ornithine + H⁺ = putrescine + CO2
• Cofactor: Pyridoxal 5'-phosphate

Pyridoxal 5'-phosphate (Bound ligand (Het Group name = PLP) matches with 93.75% similarity)

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

reference

DOI no: 10.1073/pnas.1508187112

Proc Natl Acad Sci U S A 112:11229-11234 (2015)

PubMed id: 26305948

Structural basis of antizyme-mediated regulation of polyamine homeostasis.

H.Y.Wu, S.F.Chen, J.Y.Hsieh, F.Chou, Y.H.Wang, W.T.Lin, P.Y.Lee, Y.J.Yu, L.Y.Lin, T.S.Lin, C.L.Lin, G.Y.Liu, S.R.Tzeng, H.C.Hung, N.L.Chan.

ABSTRACT

Polyamines are organic polycations essential for cell growth and differentiation; their aberrant accumulation is often associated with diseases, including many types of cancer. To maintain polyamine homeostasis, the catalytic activity and protein abundance of ornithine decarboxylase (ODC), the committed enzyme for polyamine biosynthesis, are reciprocally controlled by the regulatory proteins antizyme isoform 1 (Az1) and antizyme inhibitor (AzIN). Az1 suppresses polyamine production by inhibiting the assembly of the functional ODC homodimer and, most uniquely, by targeting ODC for ubiquitin-independent proteolytic destruction by the 26S proteasome. In contrast, AzIN positively regulates polyamine levels by competing with ODC for Az1 binding. The structural basis of the Az1-mediated regulation of polyamine homeostasis has remained elusive. Here we report crystal structures of human Az1 complexed with either ODC or AzIN. Structural analysis revealed that Az1 sterically blocks ODC homodimerization. Moreover, Az1 binding triggers ODC degradation by inducing the exposure of a cryptic proteasome-interacting surface of ODC, which illustrates how a substrate protein may be primed upon association with Az1 for ubiquitin-independent proteasome recognition. Dynamic and functional analyses further indicated that the Az1-induced binding and degradation of ODC by proteasome can be decoupled, with the intrinsically disordered C-terminal tail fragment of ODC being required only for degradation but not binding. Finally, the AzIN-Az1 structure suggests how AzIN may effectively compete with ODC for Az1 to restore polyamine production. Taken together, our findings offer structural insights into the Az-mediated regulation of polyamine homeostasis and proteasomal degradation.