PDBsum entry 4waf

Transferase/transferase inhibitor

PDB id: 4waf

Contents

Protein chains

1017 a.a.

250 a.a.

Ligands

3K6

Waters ×288

PDB id:

4waf

Name:

Transferase/transferase inhibitor

Title:

Crystal structure of a novel tetrahydropyrazolo[1,5-a]pyrazine in an engineered pi3k alpha

Structure:

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

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: pik3ca. Expressed in: trichoplusia ni. Expression_system_taxid: 7111. Expression_system_cell_line: tn5. Gene: pik3r1, grb1.

Resolution:

2.39Å R-factor: 0.202 R-free: 0.247

Authors:

M.S.Knapp,R.A.Elling

Key ref:

P.A.Barsanti et al. (2015). Structure-Based Drug Design of Novel Potent and Selective Tetrahydropyrazolo[1,5-a]pyrazines as ATR Inhibitors. Acs Med Chem Lett, 6, 37-41. PubMed id: 25589927 DOI: 10.1021/ml500353p

Date:

29-Aug-14 Release date: 31-Dec-14

Protein chain

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

Seq: 1068 a.a.

Struc: 1017 a.a.*

Protein chain

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

Seq: 724 a.a.

Struc: 250 a.a.

* PDB and UniProt seqs differ at 2 residue positions (black crosses)

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/ml500353p

Acs Med Chem Lett 6:37-41 (2015)

PubMed id: 25589927

Structure-Based Drug Design of Novel Potent and Selective Tetrahydropyrazolo[1,5-a]pyrazines as ATR Inhibitors.

P.A.Barsanti, R.J.Aversa, X.Jin, Y.Pan, Y.Lu, R.Elling, R.Jain, M.Knapp, J.Lan, X.Lin, P.Rudewicz, J.Sim, L.Taricani, G.Thomas, L.Xiao, Q.Yue.

ABSTRACT

A saturation strategy focused on improving the selectivity and physicochemical properties of ATR inhibitor HTS hit 1 led to a novel series of highly potent and selective tetrahydropyrazolo[1,5-a]pyrazines. Use of PI3Kα mutants as ATR crystal structure surrogates was instrumental in providing cocrystal structures to guide the medicinal chemistry designs. Detailed DMPK studies involving cyanide and GSH as trapping agents during microsomal incubations, in addition to deuterium-labeled compounds as mechanistic probes uncovered the molecular basis for the observed CYP3A4 TDI in the series.