PDBsum entry 1z5m

Transferase

PDB id: 1z5m

Contents

Protein chain

276 a.a. *

Ligands

SO4

LI8

GOL ×3

Metals

_CL

Waters ×74

* Residue conservation analysis

PDB id:

1z5m

Name:

Transferase

Title:

Crystal structure of n1-[3-[[5-bromo-2-[[3-[(1-pyrrolidinylcarbonyl) amino]phenyl]amino]-4-pyrimidinyl]amino]propyl]-2,2- dimethylpropanediamide complexed with human pdk1

Structure:

3-phosphoinositide dependent protein kinase-1. Chain: a. Fragment: kinase domain. Synonym: hpdk1. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: pdpk1, pdk1. Expressed in: unidentified baculovirus. Expression_system_taxid: 10469.

Resolution:

2.17Å R-factor: 0.212 R-free: 0.269

Authors:

M.Whitlow,M.Adler

Key ref:

R.I.Feldman et al. (2005). Novel small molecule inhibitors of 3-phosphoinositide-dependent kinase-1. J Biol Chem, 280, 19867-19874. PubMed id: 15772071 DOI: 10.1074/jbc.M501367200

Date:

18-Mar-05 Release date: 19-Apr-05

Protein chain

O15530  (PDPK1_HUMAN) -  3-phosphoinositide-dependent protein kinase 1 from Homo sapiens

Seq: 556 a.a.

Struc: 276 a.a.

Enzyme reactions

• Enzyme class: 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: 10.1074/jbc.M501367200

J Biol Chem 280:19867-19874 (2005)

PubMed id: 15772071

Novel small molecule inhibitors of 3-phosphoinositide-dependent kinase-1.

R.I.Feldman, J.M.Wu, M.A.Polokoff, M.J.Kochanny, H.Dinter, D.Zhu, S.L.Biroc, B.Alicke, J.Bryant, S.Yuan, B.O.Buckman, D.Lentz, M.Ferrer, M.Whitlow, M.Adler, S.Finster, Z.Chang, D.O.Arnaiz.

ABSTRACT

The phosphoinositide 3-kinase/3-phosphoinositide-dependent kinase 1 (PDK1)/Akt signaling pathway plays a key role in cancer cell growth, survival, and tumor angiogenesis and represents a promising target for anticancer drugs. Here, we describe three potent PDK1 inhibitors, BX-795, BX-912, and BX-320 (IC(50) = 11-30 nm) and their initial biological characterization. The inhibitors blocked PDK1/Akt signaling in tumor cells and inhibited the anchorage-dependent growth of a variety of tumor cell lines in culture or induced apoptosis. A number of cancer cell lines with elevated Akt activity were >30-fold more sensitive to growth inhibition by PDK1 inhibitors in soft agar than on tissue culture plastic, consistent with the cell survival function of the PDK1/Akt signaling pathway, which is particularly important for unattached cells. BX-320 inhibited the growth of LOX melanoma tumors in the lungs of nude mice after injection of tumor cells into the tail vein. The effect of BX-320 on cancer cell growth in vitro and in vivo indicates that PDK1 inhibitors may have clinical utility as anticancer agents.

Selected figure(s)

Figure 1.
FIG. 1. Compound structures for BX-795, BX-912, and BX-320.

Figure 3.
FIG. 3. Structure of BX-320 bound to the catalytic domain of PDK1 (PDB code 1Z5M [PDB] ). We crystallized the PDK1 catalytic domain (residues 51-359) as described by Biondi et al. (30). BX-320 was introduced into PDK1 crystals and the structure determined from x-ray diffraction data to a resolution 2.17 angstroms. As shown, BX-320 binds in the ATP binding pocket, making two hydrogen bonds through aminopyrimidine nitrogens to Ala^162 located in the hinge region.

The above figures are reprinted by permission from the ASBMB: J Biol Chem (2005, 280, 19867-19874) copyright 2005.

Figures were selected by an automated process.