PDBsum entry 3hdm

Transferase

PDB id: 3hdm

Contents

Protein chain

285 a.a. *

Ligands

MMG

Waters ×8

* Residue conservation analysis

PDB id:

3hdm

Name:

Transferase

Title:

Crystal structure of serum and glucocorticoid-regulated kinase 1 in complex with compound 1

Structure:

Serine/threonine-protein kinase sgk1. Chain: a. Synonym: serum/glucocorticoid-regulated kinase 1. Engineered: yes. Mutation: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: sgk, sgk1. Expressed in: unidentified baculovirus. Expression_system_taxid: 10469.

Resolution:

2.60Å R-factor: 0.220 R-free: 0.262

Authors:

B.Zhao,M.Hammond

Key ref:

M.Hammond et al. (2009). Design and synthesis of orally bioavailable serum and glucocorticoid-regulated kinase 1 (SGK1) inhibitors. Bioorg Med Chem Lett, 19, 4441-4445. PubMed id: 19497745

Date:

07-May-09 Release date: 30-Jun-09

Protein chain

O00141  (SGK1_HUMAN) -  Serine/threonine-protein kinase Sgk1 from Homo sapiens

Seq: 431 a.a.

Struc: 285 a.a.

Enzyme reactions

• Enzyme class: 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⁺

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

reference

Bioorg Med Chem Lett 19:4441-4445 (2009)

PubMed id: 19497745

Design and synthesis of orally bioavailable serum and glucocorticoid-regulated kinase 1 (SGK1) inhibitors.

M.Hammond, D.G.Washburn, H.T.Hoang, S.Manns, J.S.Frazee, H.Nakamura, J.R.Patterson, W.Trizna, C.Wu, L.M.Azzarano, R.Nagilla, M.Nord, R.Trejo, M.S.Head, B.Zhao, A.M.Smallwood, K.Hightower, N.J.Laping, C.G.Schnackenberg, S.K.Thompson.

ABSTRACT

The lead serum and glucocorticoid-related kinase 1 (SGK1) inhibitors 4-(5-phenyl-1H-pyrrolo[2,3-b]pyridin-3-yl)benzoic acid (1) and {4-[5-(2-naphthalenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]phenyl}acetic acid (2) suffer from low DNAUC values in rat, due in part to formation and excretion of glucuronic acid conjugates. These PK/glucuronidation issues were addressed either by incorporating a substituent on the 3-phenyl ring ortho to the key carboxylate functionality of 1 or by substituting on the group in between the carboxylate and phenyl ring of 2. Three of these analogs have been identified as having good SGK1 inhibition potency and have DNAUC values suitable for in vivo testing.