PDBsum entry 6qhc

Hydrolase

PDB id: 6qhc

Contents

Protein chains

222 a.a.

Ligands

GOL

135 ×2

DMS

Waters ×216

PDB id:

6qhc

Name:

Hydrolase

Title:

Crystal structure of human kallikrein 6 in complex with gsk358180b

Structure:

Kallikrein-6. Chain: a, b. Synonym: neurosin,protease m,sp59,serine protease 18,serine protease 9,zyme. Engineered: yes. Mutation: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: klk6, prss18, prss9. Expressed in: baculovirus expression vector pfastbac1-hm. Expression_system_taxid: 274590

Resolution:

1.87Å R-factor: 0.201 R-free: 0.236

Authors:

J.H.Thorpe

Key ref:

G.V.White et al. (2019). Kallikrein 5 inhibitors identified through structure based drug design in search for a treatment for Netherton Syndrome. Bioorg Med Chem Lett, 29, 821-825. PubMed id: 30691925 DOI: 10.1016/j.bmcl.2019.01.020

Date:

16-Jan-19 Release date: 06-Feb-19

Protein chains

Q92876  (KLK6_HUMAN) -  Kallikrein-6 from Homo sapiens

Seq: 244 a.a.

Struc: 222 a.a.*

* PDB and UniProt seqs differ at 3 residue positions (black crosses)

Enzyme reactions

• Enzyme class: E.C.3.4.21.- - ?????

DOI no: 10.1016/j.bmcl.2019.01.020

Bioorg Med Chem Lett 29:821-825 (2019)

PubMed id: 30691925

Kallikrein 5 inhibitors identified through structure based drug design in search for a treatment for Netherton Syndrome.

G.V.White, E.V.Edgar, D.S.Holmes, X.Q.Lewell, J.Liddle, O.Polyakova, K.J.Smith, J.H.Thorpe, A.L.Walker, Y.Wang, R.J.Young, A.Hovnanian.

ABSTRACT

Netherton syndrome (NS) is a rare and debilitating severe autosomal recessive genetic skin disease with high mortality rates particularly in neonates. NS is caused by loss-of-function SPINK5 mutations leading to unregulated kallikrein 5 (KLK5) and kallikrein 7 (KLK7) activity. Furthermore, KLK5 inhibition has been proposed as a potential therapeutic treatment for NS. Identification of potent and selective KLK5 inhibitors would enable further exploration of the disease biology and could ultimately lead to a treatment for NS. This publication describes how fragmentation of known trypsin-like serine protease (TLSP) inhibitors resulted in the identification of a series of phenolic amidine-based KLK5 inhibitors 1. X-ray crystallography was used to find alternatives to the phenol interaction leading to identification of carbonyl analogues such as lactam 13 and benzimidazole 15. These reversible inhibitors, with selectivity over KLK1 (10-100 fold), provided novel starting points for the guided growth towards suitable tool molecules for the exploration of KLK5 biology.