PDBsum entry 2bm2

Hydrolase

PDB id: 2bm2

Contents

Protein chain

243 a.a. *

Ligands

PM2 ×4

Waters ×377

* Residue conservation analysis

PDB id:

2bm2

Name:

Hydrolase

Title:

Human beta-ii tryptase in complex with 4-(3-aminomethyl-phenyl)- piperidin-1-yl-(5-phenethyl- pyridin-3-yl)-methanone

Structure:

Human beta2 tryptase. Chain: a, b, c, d. Synonym: tryptase 2, tryptase ii. Engineered: yes. Other_details: deglycosylated protein

Source:

Homo sapiens. Human. Organism_taxid: 9606. Expressed in: pichia pastoris. Expression_system_taxid: 4922

Biol. unit:

Tetramer (from PDB file)

Resolution:

2.20Å R-factor: 0.203 R-free: 0.259

Authors:

S.Maignan,J.-P.Guilloteau,A.Dupuy,J.Levell,P.Astles,P.Eastwood, J.Cairns,O.Houille,S.Aldous,G.Merriman,B.Whiteley,J.Pribish, M.Czekaj,G.Liang,J.Davidson,T.Harrison,A.Morley,S.Watson,G.Fenton, C.Mccarthy,J.Romano,R.Mathew,D.Engers,M.Gardyan,K.Sides,J.Kwong, J.Tsay,S.Rebello,L.Shen,J.Wang,Y.Luo,O.Giardino,H.-K.Lim,K.Smith, H.Pauls

Key ref:

J.Levell et al. (2005). Structure based design of 4-(3-aminomethylphenyl)piperidinyl-1-amides: novel, potent, selective, and orally bioavailable inhibitors of betaII tryptase. Bioorg Med Chem Lett, 13, 2859-2872. PubMed id: 15781396 DOI: 10.1016/j.bmc.2005.02.014

Date:

09-Mar-05 Release date: 22-Mar-05

Protein chains

P20231  (TRYB2_HUMAN) -  Tryptase beta-2 from Homo sapiens

Seq: 275 a.a.

Struc: 243 a.a.*

* PDB and UniProt seqs differ at 4 residue positions (black crosses)

Enzyme reactions

• Enzyme class: E.C.3.4.21.59 - tryptase.
• Reaction: Preferential cleavage: Arg-|-, Lys-|-, but with more restricted specificity than trypsin.

DOI no: 10.1016/j.bmc.2005.02.014

Bioorg Med Chem Lett 13:2859-2872 (2005)

PubMed id: 15781396

Structure based design of 4-(3-aminomethylphenyl)piperidinyl-1-amides: novel, potent, selective, and orally bioavailable inhibitors of betaII tryptase.

J.Levell, P.Astles, P.Eastwood, J.Cairns, O.Houille, S.Aldous, G.Merriman, B.Whiteley, J.Pribish, M.Czekaj, G.Liang, S.Maignan, J.P.Guilloteau, A.Dupuy, J.Davidson, T.Harrison, A.Morley, S.Watson, G.Fenton, C.McCarthy, J.Romano, R.Mathew, D.Engers, M.Gardyan, K.Sides, J.Kwong, J.Tsay, S.Rebello, L.Shen, J.Wang, Y.Luo, O.Giardino, H.K.Lim, K.Smith, H.Pauls.

ABSTRACT

Tryptase is a serine protease found almost exclusively in mast cells. It has trypsin-like specificity, favoring cleavage of substrates with an arginine (or lysine) at the P1 position, and has optimal catalytic activity at neutral pH. Current evidence suggests tryptase beta is the most important form released during mast cell activation in allergic diseases. It is shown to have numerous pro-inflammatory cellular activities in vitro, and in animal models tryptase provokes broncho-constriction and induces a cellular inflammatory infiltrate characteristic of human asthma. Screening of in-house inhibitors of factor Xa (a closely related serine protease) identified beta-amidoester benzamidines as potent inhibitors of recombinant human betaII tryptase. X-ray structure driven template modification and exchange of the benzamidine to optimize potency and pharmacokinetic properties gave selective, potent and orally bioavailable 4-(3-aminomethyl phenyl)piperidinyl-1-amides.