PDBsum entry 4ykn

Transferase/transferase inhibitor

PDB id: 4ykn

Contents

Protein chain

1205 a.a.

Ligands

4EL ×3

Waters ×94

PDB id:

4ykn

Name:

Transferase/transferase inhibitor

Title:

Pi3k alpha lipid kinase with active site inhibitor

Structure:

Phosphatidylinositol 3-kinase regulatory subunit alpha, phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform fusion protein. Chain: a. Fragment: unp p27986 residues 318-615, linker (gspgisggggg), p42336 residues 2-1068. Synonym: ptdins-3-kinase regulatory subunit alpha, phosphatidylinositol 3-kinase 85 kda regulatory subunit alpha,ptdins- 3-kinase regulatory subunit p85-alpha,ptdins-3-kinase subunit alpha,

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: pik3r1, grb1, pik3ca. Expressed in: unidentified baculovirus. Expression_system_taxid: 10469

Resolution:

2.90Å R-factor: 0.204 R-free: 0.247

Authors:

P.A.Elkins

Key ref:

H.Yang et al. (2015). Discovery of a Potent Class of PI3Kα Inhibitors with Unique Binding Mode via Encoded Library Technology (ELT). Acs Med Chem Lett, 6, 531-536. PubMed id: 26005528 DOI: 10.1021/acsmedchemlett.5b00025

Date:

04-Mar-15 Release date: 17-Jun-15

Protein chain

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

Seq: 724 a.a.

Struc: 1205 a.a.*

Protein chain

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

Seq: 1068 a.a.

Struc: 1205 a.a.*

* PDB and UniProt seqs differ at 141 residue positions (black crosses)

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⁺

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/acsmedchemlett.5b00025

Acs Med Chem Lett 6:531-536 (2015)

PubMed id: 26005528

Discovery of a Potent Class of PI3Kα Inhibitors with Unique Binding Mode via Encoded Library Technology (ELT).

H.Yang, P.F.Medeiros, K.Raha, P.Elkins, K.E.Lind, R.Lehr, N.D.Adams, J.L.Burgess, S.J.Schmidt, S.D.Knight, K.R.Auger, M.D.Schaber, G.J.Franklin, Y.Ding, J.L.DeLorey, P.A.Centrella, S.Mataruse, S.R.Skinner, M.A.Clark, J.W.Cuozzo, G.Evindar.

ABSTRACT

In the search of PI3K p110α wild type and H1047R mutant selective small molecule leads, an encoded library technology (ELT) campaign against the desired target proteins was performed which led to the discovery of a selective chemotype for PI3K isoforms from a three-cycle DNA encoded library. An X-ray crystal structure of a representative inhibitor from this chemotype demonstrated a unique binding mode in the p110α protein.