PDBsum entry 3e5a

Transferase

PDB id: 3e5a

Contents

Protein chains

265 a.a. *

33 a.a. *

Ligands

VX6

SO4

Waters ×58

* Residue conservation analysis

PDB id:

3e5a

Name:

Transferase

Title:

Crystal structure of aurora a in complex with vx-680 and tpx2

Structure:

Serine/threonine-protein kinase 6. Chain: a. Fragment: residues 122-403. Synonym: aurora kinase a, aurora-a, serine/threonine kinase 15, aurora/ipl1-related kinase 1, aurora-related kinase 1, hark1, breast tumor-amplified kinase. Engineered: yes. Targeting protein for xklp2. Chain: b.

Source:

Homo sapiens. Organism_taxid: 9606. Gene: aurka, aik, ark1, aura, btak, stk15, stk6. Expressed in: escherichia coli. Gene: tpx2, c20orf1, c20orf2, dil2, hca519.

Resolution:

2.30Å R-factor: 0.206 R-free: 0.256

Authors:

B.Zhao,A.Smallwood,Z.Lai

Key ref:

B.Zhao et al. (2008). Modulation of kinase-inhibitor interactions by auxiliary protein binding: crystallography studies on Aurora A interactions with VX-680 and with TPX2. Protein Sci, 17, 1791-1797. PubMed id: 18662907 DOI: 10.1110/ps.036590.108

Date:

13-Aug-08 Release date: 28-Oct-08

Protein chain

O14965  (AURKA_HUMAN) -  Aurora kinase A from Homo sapiens

Seq: 403 a.a.

Struc: 265 a.a.*

Protein chain

Q9ULW0  (TPX2_HUMAN) -  Targeting protein for Xklp2 from Homo sapiens

Seq: 747 a.a.

Struc: 33 a.a.

* PDB and UniProt seqs differ at 1 residue position (black cross)

Enzyme reactions

• Enzyme class: Chain A: E.C.2.7.11.1 - non-specific serine/threonine protein kinase.
• Reaction:
  1. L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP + H⁺
  2. L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein] + ADP + H⁺

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

reference

DOI no: 10.1110/ps.036590.108

Protein Sci 17:1791-1797 (2008)

PubMed id: 18662907

Modulation of kinase-inhibitor interactions by auxiliary protein binding: crystallography studies on Aurora A interactions with VX-680 and with TPX2.

B.Zhao, A.Smallwood, J.Yang, K.Koretke, K.Nurse, A.Calamari, R.B.Kirkpatrick, Z.Lai.

ABSTRACT

VX-680, also known as MK-0457, is an ATP-competitive small molecule inhibitor of the Aurora kinases that has entered phase II clinical trials for the treatment of cancer. We have solved the cocrystal structure of AurA/TPX2/VX-680 at 2.3 A resolution. In the crystal structure, VX-680 binds to the active conformation of AurA. The glycine-rich loop in AurA adopts a unique bent conformation, forming a pi-pi interaction with the phenyl group of VX-680. In contrast, in the published AurA/VX-680 structure, VX-680 binds to AurA in the inactive conformation, interacting with a hydrophobic pocket only present in the inactive conformation. These data suggest that TPX2, a protein cofactor, can alter the binding mode of VX-680 with AurA. More generally, the presence of physiologically relevant cofactor proteins can alter the kinetics, binding interactions, and inhibition of enzymes, and studies with these multiprotein complexes may be beneficial to the discovery and optimization of enzyme inhibitors as therapeutic agents.

Selected figure(s)

Figure 2.
Binding of VX-680 in the active site of AurA/TPX2. (A) The electron density of VX-680 contoured at 1.5[sigma] from the final 2fo-fc map. The AurA carbons are shown in green, inhibitor carbons in yellow, oxygens in red, nitrogens in blue, sulfur in orange, and water molecules in light blue. (B) Interactions of VX-680 with the active site of AurA when TPX2 is bound. The backbone tracing is in gray and hydrogen bonds are shown as dotted black lines. (C) Interactions of VX-680 with the active site of AurA without TPX2 bound (adapted from Cheetham et al. 2007 and reprinted with permission from Elsevier [copyright]2007).

Figure 3.
Superposition of the backbones of AurA/TPX2/VX-680 (gold) and AurA/TPX2/ADP (gray, pdb: 1ol5) structures focusing on the different conformations of the glycine-rich loop. The C[alpha] of Phe144^AUR in the AurA/TPX2/VX-680 structure has moved by >8 A. The VX-680 carbons are in yellow, the ADP carbons in green, oxygens in red, nitrogens in blue, sulfur and phosphorus in orange. The side chain of Phe144 is shown in stick form.

The above figures are reprinted from an Open Access publication published by the Protein Society: Protein Sci (2008, 17, 1791-1797) copyright 2008.

Figures were selected by an automated process.