PDBsum entry 4l2y

Signaling protein/transferase/inhibitor

PDB id: 4l2y

Contents

Protein chains

991 a.a.

277 a.a.

Ligands

XXK

SO4 ×2

GOL

Waters ×17

PDB id:

4l2y

Name:

Signaling protein/transferase/inhibitor

Title:

Crystal structure of p110alpha complexed with nish2 of p85alpha and compound 9d

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:

2.80Å R-factor: 0.218 R-free: 0.271

Authors:

J.Zhang,Y.L.Zhao,Y.Y.Chen,M.Huang,F.Jiang

Key ref:

Y.Zhao et al. (2014). Crystal Structures of PI3Kα Complexed with PI103 and Its Derivatives: New Directions for Inhibitors Design. Acs Med Chem Lett, 5, 138-142. PubMed id: 24900786 DOI: 10.1021/ml400378e

Date:

05-Jun-13 Release date: 01-Jan-14

Protein chain

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

Seq: 1068 a.a.

Struc: 991 a.a.

Protein chain

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

Seq: 724 a.a.

Struc: 277 a.a.

Enzyme reactions

• Enzyme class 2: 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 3: Chain A: 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: 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⁺

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/ml400378e

Acs Med Chem Lett 5:138-142 (2014)

PubMed id: 24900786

Crystal Structures of PI3Kα Complexed with PI103 and Its Derivatives: New Directions for Inhibitors Design.

Y.Zhao, X.Zhang, Y.Chen, S.Lu, Y.Peng, X.Wang, C.Guo, A.Zhou, J.Zhang, Y.Luo, Q.Shen, J.Ding, L.Meng, J.Zhang.

ABSTRACT

The phosphatidylinositol 3-kinase (PI3K) signaling pathway plays important roles in cell proliferation, growth, and survival. Hyperactivated PI3K is frequently found in a wide variety of human cancers, validating it as a promising target for cancer therapy. We determined the crystal structure of the human PI3Kα-PI103 complex to unravel molecular interactions. Based on the structure, substitution at the R1 position of the phenol portion of PI103 was demonstrated to improve binding affinity via forming a new H-bond with Lys802 at the bottom of the ATP catalytic site. Interestingly, the crystal structure of the PI3Kα-9d complex revealed that the flexibility of Lys802 can also induce additional space at the catalytic site for further modification. Thus, these crystal structures provide a molecular basis for the strong and specific interactions and demonstrate the important role of Lys802 in the design of novel PI3Kα inhibitors.