8q6h

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HUMAN PI4KIIIB IN COMPLEX WITH COVALENTLY BOUND INHIBITOR (COMPOUND 11)HUMAN PI4KIIIB IN COMPLEX WITH COVALENTLY BOUND INHIBITOR (COMPOUND 11)

Structural highlights

8q6h is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 1.94Å
Ligands:, ,
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

PI4KB_HUMAN Phosphorylates phosphatidylinositol (PI) in the first committed step in the production of the second messenger inositol-1,4,5,-trisphosphate (PIP). May regulate Golgi disintegration/reorganization during mitosis, possibly via its phosphorylation. Involved in Golgi-to-plasma membrane trafficking (By similarity).[1] [2] [3]

Publication Abstract from PubMed

The synthesis and characterisation of fluorosulfate covalent inhibitors of the lipid kinase PI4KIIIbeta is described. The conserved lysine residue located within the ATP binding site was targeted, and optimised compounds based upon reversible inhibitors with good activity and physicochemical profile showed strong reversible interactions and slow onset times for the covalent inhibition, resulting in an excellent selectivity profile for the lipid kinase target. X-Ray crystallography demonstrated a distal tyrosine residue could also be targeted using a fluorosulfate strategy. Combination of this knowledge showed that a dual covalent inhibitor could be developed which reveals potential in addressing the challenges associated with drug resistant mutations.

Covalent targeting of non-cysteine residues in PI4KIIIbeta.,Cosgrove B, Grant EK, Bertrand S, Down KD, Somers DO, P Evans J, Tomkinson NCO, Barker MD RSC Chem Biol. 2023 Oct 17;4(12):1111-1122. doi: 10.1039/d3cb00142c. eCollection , 2023 Nov 29. PMID:38033723[4]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

  1. ↑ Suzuki K, Hirano H, Okutomi K, Suzuki M, Kuga Y, Fujiwara T, Kanemoto N, Isono K, Horie M. Identification and characterization of a novel human phosphatidylinositol 4-kinase. DNA Res. 1997 Aug 31;4(4):273-80. PMID:9405935
  2. ↑ Godi A, Pertile P, Meyers R, Marra P, Di Tullio G, Iurisci C, Luini A, Corda D, De Matteis MA. ARF mediates recruitment of PtdIns-4-OH kinase-beta and stimulates synthesis of PtdIns(4,5)P2 on the Golgi complex. Nat Cell Biol. 1999 Sep;1(5):280-7. PMID:10559940 doi:http://dx.doi.org/10.1038/12993
  3. ↑ Heilmeyer LM Jr, Vereb G Jr, Vereb G, Kakuk A, Szivak I. Mammalian phosphatidylinositol 4-kinases. IUBMB Life. 2003 Feb;55(2):59-65. PMID:12749687 doi:http://dx.doi.org/10.1002/tbmb.718540873
  4. ↑ Cosgrove B, Grant EK, Bertrand S, Down KD, Somers DO, P Evans J, Tomkinson NCO, Barker MD. Covalent targeting of non-cysteine residues in PI4KIIIβ. RSC Chem Biol. 2023 Oct 17;4(12):1111-1122. PMID:38033723 doi:10.1039/d3cb00142c

8q6h, resolution 1.94Å

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