PDBsum entry 6yv0

Hydrolase

PDB id: 6yv0

Contents

Protein chain

359 a.a.

Ligands

SO4

EDO ×4

PQT

NAG

Waters ×109

PDB id:

6yv0

Name:

Hydrolase

Title:

Structure of the wnt deacylase notum in complex with a pyrrolidine-3- carboxylic acid fragment 587

Structure:

Palmitoleoyl-protein carboxylesterase notum. Chain: a. Synonym: hnotum. Engineered: yes. Mutation: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: notum, ok/sw-cl.30. Expressed in: homo sapiens. Expression_system_taxid: 9606. Expression_system_cell_line: hek293s gnti-. Expression_system_atcc_number: crl-3022

Resolution:

2.00Å R-factor: 0.213 R-free: 0.234

Authors:

R.R.Ruza,J.Hillier,E.Y.Jones

Key ref:

W.Mahy et al. (2020). Screening of a Custom-Designed Acid Fragment Library Identifies 1-Phenylpyrroles and 1-Phenylpyrrolidines as Inhibitors of Notum Carboxylesterase Activity. J Med Chem, 63, 9464-9483. PubMed id: 32787107 DOI: 10.1021/acs.jmedchem.0c00660

Date:

27-Apr-20 Release date: 13-May-20

Protein chain

Q6P988  (NOTUM_HUMAN) -  Palmitoleoyl-protein carboxylesterase NOTUM from Homo sapiens

Seq: 496 a.a.

Struc: 359 a.a.*

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

Enzyme reactions

• Enzyme class: E.C.3.1.1.98 - [Wnt protein] O-palmitoleoyl-L-serine hydrolase.
• Reaction: [Wnt protein]-O-(9Z)-hexadecenoyl-L-serine + H2O = [Wnt protein]-L-serine + (9Z)-hexadecenoate + H⁺

DOI no: 10.1021/acs.jmedchem.0c00660

J Med Chem 63:9464-9483 (2020)

PubMed id: 32787107

Screening of a Custom-Designed Acid Fragment Library Identifies 1-Phenylpyrroles and 1-Phenylpyrrolidines as Inhibitors of Notum Carboxylesterase Activity.

W.Mahy, M.Patel, D.Steadman, H.L.Woodward, B.N.Atkinson, F.Svensson, N.J.Willis, A.Flint, D.Papatheodorou, Y.Zhao, L.Vecchia, R.R.Ruza, J.Hillier, S.Frew, A.Monaghan, A.Costa, M.Bictash, M.W.Walter, E.Y.Jones, P.V.Fish.

ABSTRACT

The Wnt family of proteins are secreted signaling proteins that play key roles in regulating cellular functions. Recently, carboxylesterase Notum was shown to act as a negative regulator of Wnt signaling by mediating the removal of an essential palmitoleate. Here we disclose two new chemical scaffolds that inhibit Notum enzymatic activity. Our approach was to create a fragment library of 250 acids for screening against Notum in a biochemical assay followed by structure determination by X-ray crystallography. Twenty fragments were identified as hits for Notum inhibition, and 14 of these fragments were shown to bind in the palmitoleate pocket of Notum. Optimization of 1-phenylpyrrole 20, guided by structure-based drug design, identified 20z as the most potent compound from this series. Similarly, the optimization of 1-phenylpyrrolidine 8 gave acid 26. This work demonstrates that inhibition of Notum activity can be achieved by small, drug-like molecules possessing favorable in vitro ADME profiles.