PDBsum entry 6skb

Hydrolase

PDB id: 6skb

Contents

Protein chains

223 a.a.

Ligands

LH5 ×3

RH5 ×3

GOL

Waters ×273

PDB id:

6skb

Name:

Hydrolase

Title:

Crystal structure of human kallikrein 6 (n217d/i218y/k224r) in complex with gsk3496783a

Structure:

Kallikrein-6. Chain: a, b, c. 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:

1.84Å R-factor: 0.197 R-free: 0.229

Authors:

J.H.Thorpe

Key ref:

A.L.Walker et al. (2019). Design and development of a series of borocycles as selective, covalent kallikrein 5 inhibitors. Bioorg Med Chem Lett, 29, 126675. PubMed id: 31521475 DOI: 10.1016/j.bmcl.2019.126675

Date:

15-Aug-19 Release date: 25-Sep-19

Protein chains

Q92876  (KLK6_HUMAN) -  Kallikrein-6 from Homo sapiens

Seq: 244 a.a.

Struc: 223 a.a.*

* PDB and UniProt seqs differ at 6 residue positions (black crosses)

Enzyme reactions

• Enzyme class: E.C.3.4.21.- - ?????

DOI no: 10.1016/j.bmcl.2019.126675

Bioorg Med Chem Lett 29:126675 (2019)

PubMed id: 31521475

Design and development of a series of borocycles as selective, covalent kallikrein 5 inhibitors.

A.L.Walker, A.Denis, R.P.Bingham, A.Boulliot, E.V.Edgar, A.Ferrie, D.S.Holmes, A.Laroze, J.Liddle, M.H.Fouchet, A.Moquette, P.Nassau, A.C.Pearce, O.Polyakova, K.J.Smith, P.Thomas, J.H.Thorpe, L.Trottet, Y.Wang, A.Hovnanian.

ABSTRACT

The connection between Netherton syndrome and overactivation of epidermal/dermal proteases, particularly Kallikrein 5 (KLK5) has been well established and it is expected that a KLK5 inhibitor would improve the dermal barrier and also reduce the pain and itch that afflict Netherton syndrome patients. One of the challenges of covalent protease inhibitors has been achieving selectivity over closely related targets. In this paper we describe the use of structural insight to design and develop a selective and highly potent reversibly covalent KLK5 inhibitor from an initial weakly binding fragment.