PDBsum entry 1kyn

Hydrolase

PDB id

1kyn

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Contents

			Protein chain

					223 a.a. *

			Ligands

					KTP ×2

* Residue conservation analysis

PDB id:

1kyn

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Name:

Hydrolase

Title:

Cathepsin-g

Structure:

Cathepsin g. Chain: a, b. Synonym: cg. Ec: 3.4.21.20

Source:

Homo sapiens. Human. Organism_taxid: 9606

Resolution:

3.50Å

R-factor:

0.258

R-free:

0.328

Authors:

M.N.Greco,M.J.Hawkins,E.T.Powell,H.R.Almond Jr.,T.W.Corcoran,L.De Garavilla,J.A.Kauffman,R.Recacha,D.Chattopadhyay,P.Andrade-Gordon, B.E.Maryanoff

Key ref:

M.N.Greco et al. (2002). Nonpeptide inhibitors of cathepsin G: optimization of a novel beta-ketophosphonic acid lead by structure-based drug design. J Am Chem Soc, 124, 3810-3811. PubMed id: 11942800 DOI: 10.1021/ja017506h

Date:

05-Feb-02

Release date:

01-May-02

PROCHECK

	Headers

	References

Protein chains

P08311 (CATG_HUMAN) - Cathepsin G from Homo sapiens

Seq: Struc:					255 a.a. 223 a.a.

Key:

PfamA domain

Secondary structure

CATH domain



		Enzyme reactions

Enzyme class:

E.C.3.4.21.20 - cathepsin G.

[IntEnz] [ExPASy] [KEGG] [BRENDA]

Reaction:

Specificity similar to chymotrypsin C.

DOI no: 10.1021/ja017506h	J Am Chem Soc 124:3810-3811 (2002)
PubMed id: 11942800

Nonpeptide inhibitors of cathepsin G: optimization of a novel beta-ketophosphonic acid lead by structure-based drug design.
M.N.Greco, M.J.Hawkins, E.T.Powell, H.R.Almond, T.W.Corcoran, L.de Garavilla, J.A.Kauffman, R.Recacha, D.Chattopadhyay, P.Andrade-Gordon, B.E.Maryanoff.

ABSTRACT

The serine protease cathepsin G (EC 3.4.21.20; Cat G), which is stored in the azurophilic granules of neutrophils (polymorphonuclear leukocytes) and released on degranulation, has been implicated in various pathological conditions associated with inflammation. By employing high-throughput screening, we identified beta-ketophosphonic acid 1 as a moderate inhibitor of Cat G (IC(50) = 4.1 microM). We were fortunate to obtain a cocrystal of 1 with Cat G and solve its structure by X-ray crystallography (3.5 A). Structural details from the X-ray analysis of 1.Cat G served as a platform for optimization of this lead compound by structure-based drug design. With the aid of molecular modeling, substituents were attached to the 3-position of the 2-naphthyl ring of 1, which occupies the S1 pocket of Cat G, to provide an extension into the hydrophobic S3 region. Thus, we arrived at analogue 7 with an 80-fold potency improvement over 1 (IC(50) = 53 nM). From these results, it is evident that the beta-ketophosphonic acid unit can form the basis for a novel class of serine protease inhibitors.

Literature references that cite this PDB file's key reference

PubMed id

Reference

15927073

J.W.Golden, and L.A.Schiff (2005).
Neutrophil elastase, an acid-independent serine protease, facilitates reovirus uncoating and infection in U937 promonocyte cells.

Virol J, 2, 48.

15741158

L.de Garavilla, M.N.Greco, N.Sukumar, Z.W.Chen, A.O.Pineda, F.S.Mathews, E.Di Cera, E.C.Giardino, G.I.Wells, B.J.Haertlein, J.A.Kauffman, T.W.Corcoran, C.K.Derian, A.J.Eckardt, B.P.Damiano, P.Andrade-Gordon, and B.E.Maryanoff (2005).
A novel, potent dual inhibitor of the leukocyte proteases cathepsin G and chymase: molecular mechanisms and anti-inflammatory activity in vivo.

J Biol Chem, 280, 18001-18007.

PDB codes:

1t31 1t32

15155131

M.Braddock (2004).
2nd International Conference on Immune-Mediated Diseases & 8th International Anti-Inflammation Meeting.

Expert Opin Investig Drugs, 13, 555-564.

The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time. Where a reference describes a PDB structure, the PDB codes are shown on the right.