PDBsum entry 2v4l

Transferase

PDB id: 2v4l

Contents

Protein chain

845 a.a. *

Ligands

ABJ

Waters ×50

* Residue conservation analysis

PDB id:

2v4l

Name:

Transferase

Title:

Complex of human phosphoinositide 3-kinase catalytic subunit gamma (p110 gamma) with pik-284

Structure:

Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit gamma isoform. Chain: a. Fragment: catalytic subunit, residues 144-1102. Synonym: pi3-kinase p110 subunit gamma, ptdins-3-kinase subunit p110, pi3kgamma, p120-pi3k, pi3k, phosphoinositide 3-kinase gamma. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108.

Resolution:

2.50Å R-factor: 0.250 R-free: 0.296

Authors:

B.Apsel,B.Gonzalez,J.A.Blair,T.M.Nazif,M.E.Feldman,R.L.Williams, K.M.Shokat,Z.A.Knight

Key ref:

B.Apsel et al. (2008). Targeted polypharmacology: discovery of dual inhibitors of tyrosine and phosphoinositide kinases. Nat Chem Biol, 4, 691-699. PubMed id: 18849971 DOI: 10.1038/nchembio.117

Date:

25-Sep-08 Release date: 14-Oct-08

Protein chain

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

Seq: 1102 a.a.

Struc: 845 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: 10.1038/nchembio.117

Nat Chem Biol 4:691-699 (2008)

PubMed id: 18849971

Targeted polypharmacology: discovery of dual inhibitors of tyrosine and phosphoinositide kinases.

B.Apsel, J.A.Blair, B.Gonzalez, T.M.Nazif, M.E.Feldman, B.Aizenstein, R.Hoffman, R.L.Williams, K.M.Shokat, Z.A.Knight.

ABSTRACT

The clinical success of multitargeted kinase inhibitors has stimulated efforts to identify promiscuous drugs with optimal selectivity profiles. It remains unclear to what extent such drugs can be rationally designed, particularly for combinations of targets that are structurally divergent. Here we report the systematic discovery of molecules that potently inhibit both tyrosine kinases and phosphatidylinositol-3-OH kinases, two protein families that are among the most intensely pursued cancer drug targets. Through iterative chemical synthesis, X-ray crystallography and kinome-level biochemical profiling, we identified compounds that inhibit a spectrum of new target combinations in these two families. Crystal structures revealed that the dual selectivity of these molecules is controlled by a hydrophobic pocket conserved in both enzyme classes and accessible through a rotatable bond in the drug skeleton. We show that one compound, PP121, blocks the proliferation of tumor cells by direct inhibition of oncogenic tyrosine kinases and phosphatidylinositol-3-OH kinases. These molecules demonstrate the feasibility of accessing a chemical space that intersects two families of oncogenes.

Selected figure(s)

Figure 2.
(a) Experimental strategy for the discovery of dual inhibitors, and IC[50] values ( M) for 8 molecules tested against 14 tyrosine kinases and PI(3)Ks (10 M ATP). IC[50] values less than 0.1 M are shaded red. Pyrazolopyrimidine N4 and N5, which make hydrogen bonds to the kinase, are labeled. (b) Percentage inhibition of 84 tyrosine kinases (right) and 135 serine-threonine kinases (left) by 7 inhibitors from this study (right columns) and 5 reference compounds (left columns). PP inhibitors were tested at 1 M drug and, typically, 10 M ATP. Data from the Invitrogen SelectScreen assay. (c) Principal component analysis of the target selectivity of 172 pyrazolopyrimidine inhibitors and 8 reference compounds. Key compounds are labeled.

Figure 4.
(a) Correlation between IC[50] values for inhibitors against Src (x axis) and either Hck or the gatekeeper mutant Src T338I (y axis). (b) Binding orientation of S1 relative to ATP in c-Src (top) and p110 (bottom). (c) Overlay of cocrystal structures of inhibitors bound to c-Src (protein colored red, drugs orange: S1, PP102, PP121 and PP494) and p110 (protein blue, compounds gray: S1 and S2). The gatekeeper residues Thr338 (c-Src) and Ile879 (p110 ) are highlighted. (d) Top, the catalytic lysine (Lys295) makes a hydrogen bond to Glu310 in active c-Src. Center, helix C and Glu310 are disordered in c-Src structures containing PP102. Bottom, PP121 makes a hydrogen bond to Glu310 and orders helix C when bound to c-Src.

The above figures are reprinted by permission from Macmillan Publishers Ltd: Nat Chem Biol (2008, 4, 691-699) copyright 2008.

Figures were selected by an automated process.