PDBsum entry 4jps

Transferase/transferase inhibitor

PDB id: 4jps

Contents

Protein chains

999 a.a.

227 a.a.

Ligands

SCN

1LT

Waters ×506

PDB id:

4jps

Name:

Transferase/transferase inhibitor

Title:

Co-crystal structures of the lipid kinase pi3k alpha with pan and isoform selective inhibitors

Structure:

Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform. Chain: a. Synonym: pi3-kinase subunit alpha, pi3k-alpha, pi3kalpha, ptdins-3- kinase subunit alpha, phosphatidylinositol 4,5-bisphosphate 3-kinase 110 kda catalytic subunit alpha, ptdins-3-kinase subunit p110-alpha, p110alpha, phosphoinositide-3-kinase catalytic alpha polypeptide, serine/threonine protein kinase pik3ca. Engineered: yes.

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: pik3ca. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108. Gene: grb1, pik3r1.

Resolution:

2.20Å R-factor: 0.206 R-free: 0.228

Authors:

M.S.Knapp,R.A.Elling

Key ref:

P.Furet et al. (2013). Discovery of NVP-BYL719 a potent and selective phosphatidylinositol-3 kinase alpha inhibitor selected for clinical evaluation. Bioorg Med Chem Lett, 23, 3741-3748. PubMed id: 23726034 DOI: 10.1016/j.bmcl.2013.05.007

Date:

19-Mar-13 Release date: 02-Apr-14

Protein chain

P42336  (PK3CA_HUMAN) -  Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform from Homo sapiens

Seq: 1068 a.a.

Struc: 999 a.a.

Protein chain

P27986  (P85A_HUMAN) -  Phosphatidylinositol 3-kinase regulatory subunit alpha from Homo sapiens

Seq: 724 a.a.

Struc: 227 a.a.

Enzyme reactions

• Enzyme class 2: Chain A: E.C.2.7.1.137 - phosphatidylinositol 3-kinase.
• Pathway: 1-Phosphatidyl-myo-inositol Metabolism
• 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 3: Chain A: 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 4: 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⁺
• Enzyme class 5: Chain B: E.C.?

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: 10.1016/j.bmcl.2013.05.007

Bioorg Med Chem Lett 23:3741-3748 (2013)

PubMed id: 23726034

Discovery of NVP-BYL719 a potent and selective phosphatidylinositol-3 kinase alpha inhibitor selected for clinical evaluation.

P.Furet, V.Guagnano, R.A.Fairhurst, P.Imbach-Weese, I.Bruce, M.Knapp, C.Fritsch, F.Blasco, J.Blanz, R.Aichholz, J.Hamon, D.Fabbro, G.Caravatti.

ABSTRACT

Phosphatidylinositol-3-kinase α (PI3Kα) is a therapeutic target of high interest in anticancer drug research. On the basis of a binding model rationalizing the high selectivity and potency of a particular series of 2-aminothiazole compounds in inhibiting PI3Kα, a medicinal chemistry program has led to the discovery of the clinical candidate NVP-BYL719.