PDBsum entry 4ps3

Transferase/transferase inhibitor

PDB id: 4ps3

Contents

Protein chain

843 a.a.

Ligands

2WH

Waters ×6

PDB id:

4ps3

Name:

Transferase/transferase inhibitor

Title:

Structure of pi3k gamma in complex with 1-[6-(5-methoxypyridin-3-yl)- 1,3-benzothiazol-2-yl]-3-[2-(1-propyl-1h-imidazol-4-yl)ethyl]urea

Structure:

Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma isoform. Chain: a. Fragment: catalytic domain (unp residues 144-1102). Synonym: pi3-kinase subunit gamma, pi3k-gamma, pi3kgamma, ptdins-3- kinase subunit gamma, phosphatidylinositol 4,5-bisphosphate 3-kinase 110 kda catalytic subunit gamma, ptdins-3-kinase subunit p110-gamma, p110gamma, phosphoinositide-3-kinase catalytic gamma polypeptide, serine/threonine protein kinase pik3cg, p120-pi3k.

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: pi3k gamma, pik3cg. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108. Expression_system_cell_line: sf21.

Resolution:

2.90Å R-factor: 0.214 R-free: 0.259

Authors:

J.P.Griffith

Key ref:

P.N.Collier et al. (2015). Structural basis for isoform selectivity in a class of benzothiazole inhibitors of phosphoinositide 3-kinase γ. J Med Chem, 58, 517-521. PubMed id: 24754609 DOI: 10.1021/jm500362j

Date:

06-Mar-14 Release date: 14-May-14

Protein chain

P48736  (PK3CG_HUMAN) -  Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma isoform from Homo sapiens

Seq: 1102 a.a.

Struc: 843 a.a.*

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

Enzyme reactions

• Enzyme class 2: 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⁺
• Enzyme class 3: E.C.2.7.1.137 - phosphatidylinositol 3-kinase.

Pathway:

• Reaction: a 1,2-diacyl-sn-glycero-3-phospho-(1D-myo-inositol) + ATP = a 1,2-diacyl- sn-glycero-3-phospho-(1D-myo-inositol-3-phosphate) + ADP + H⁺
• Enzyme class 4: E.C.2.7.1.153 - phosphatidylinositol-4,5-bisphosphate 3-kinase.

Pathway:

• Reaction: a 1,2-diacyl-sn-glycero-3-phospho-(1D-myo-inositol-4,5-bisphosphate) + ATP = a 1,2-diacyl-sn-glycero-3-phospho-(1D-myo-inositol-3,4,5- trisphosphate) + ADP + H⁺
• Enzyme class 5: E.C.2.7.1.154 - phosphatidylinositol-4-phosphate 3-kinase.

Pathway:

• Reaction: a 1,2-diacyl-sn-glycero-3-phospho-(1D-myo-inositol 4-phosphate) + ATP = a 1,2-diacyl-sn-glycero-3-phospho-(1D-myo-inositol-3,4-bisphosphate) + ADP + H⁺

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.

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

reference

DOI no: 10.1021/jm500362j

J Med Chem 58:517-521 (2015)

PubMed id: 24754609

Structural basis for isoform selectivity in a class of benzothiazole inhibitors of phosphoinositide 3-kinase γ.

P.N.Collier, G.Martinez-Botella, M.Cornebise, K.M.Cottrell, J.D.Doran, J.P.Griffith, S.Mahajan, F.Maltais, C.S.Moody, E.P.Huck, T.Wang, A.M.Aronov.

ABSTRACT

Phosphoinositide 3-kinase γ (PI3Kγ) is an attractive target to potentially treat a range of disease states. Herein, we describe the evolution of a reported phenylthiazole pan-PI3K inhibitor into a family of potent and selective benzothiazole inhibitors. Using X-ray crystallography, we discovered that compound 22 occupies a previously unreported hydrophobic binding cleft adjacent to the ATP binding site of PI3Kγ, and achieves its selectivity by exploiting natural sequence differences among PI3K isoforms in this region.