 |
PDBsum entry 5nrf
|
|
|
|
PDB id:
|
|
|
|
| Name: |
|
Hydrolase
|
|
|
Title:
|
|
Crystal structure of human chitotriosidase-1 (hchit) catalytic domain in complex with compound 7i
|
|
Structure:
|
|
Chitotriosidase-1. Chain: a. Synonym: chitinase-1. Engineered: yes
|
|
Source:
|
|
Homo sapiens. Human. Organism_taxid: 9606. Gene: chit1. Expressed in: homo sapiens. Expression_system_taxid: 9606
|
|
Resolution:
|
|
|
1.45Å
|
R-factor:
|
0.145
|
R-free:
|
0.169
|
|
|
Authors:
|
|
M.Mazur,J.Olczak,S.Olejniczak,R.Koralewski,W.Czestkowski, A.Jedrzejczak,J.Golab,K.Dzwonek,B.Dymek,P.Sklepkiewicz,A.Zagozdzon, T.Noonan,K.Mahboubi,B.Conway,R.Sheeler,P.Beckett,W.M.Hungerford, A.Podjarny,A.Mitschler,A.Cousido-Siah,F.Fadel,A.Golebiowski
|
|
Key ref:
|
|
M.Mazur
et al.
(2018).
Targeting Acidic Mammalian chitinase Is Effective in Animal Model of Asthma.
J Med Chem,
61,
695-710.
PubMed id:
DOI:
|
|
|
Date:
|
|
|
22-Apr-17
|
Release date:
|
28-Mar-18
|
|
|
|
|
|
|
PROCHECK
|
|
|
|
|
|
Headers
|
|
|
|
References
|
|
|
|
|
|
|
|
Q13231
(CHIT1_HUMAN) -
Chitotriosidase-1 from Homo sapiens
|
|
|
|
Seq:
Struc:
|
|
|
|
466 a.a.
377 a.a.*
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Key: |
|
 |
Secondary structure |
|
|
*
PDB and UniProt seqs differ
at 9 residue positions (black
crosses)
|
|
|
|
|
|
|
|
|
|
|
|
|
Enzyme class:
|
|
E.C.3.2.1.14
- chitinase.
|
|
|
|
|
|
|
Reaction:
|
|
Hydrolysis of the 1,4-beta-linkages of N-acetyl-D-glucosamine polymers of chitin.
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
 |
|
|
|
|
|
|
| |
|
DOI no:
|
J Med Chem
61:695-710
(2018)
|
|
PubMed id:
|
|
|
|
|
|
| |
|
Targeting Acidic Mammalian chitinase Is Effective in Animal Model of Asthma.
|
|
M.Mazur,
J.Olczak,
S.Olejniczak,
R.Koralewski,
W.Czestkowski,
A.Jedrzejczak,
J.Golab,
K.Dzwonek,
B.Dymek,
P.L.Sklepkiewicz,
A.Zagozdzon,
T.Noonan,
K.Mahboubi,
B.Conway,
R.Sheeler,
P.Beckett,
W.M.Hungerford,
A.Podjarny,
A.Mitschler,
A.Cousido-Siah,
F.Fadel,
A.Golebiowski.
|
|
|
|
|
| |
ABSTRACT
|
|
|
|
| |
|
|
This article highlights our work toward the identification of a potent,
selective, and efficacious acidic mammalian chitinase (AMCase) inhibitor.
Rational design, guided by X-ray analysis of several inhibitors bound to human
chitotriosidase (hCHIT1), led to the identification of compound 7f as a highly
potent AMCase inhibitor (IC50values of 14 and 19 nM against human and
mouse enzyme, respectively) and selective (>150× against mCHIT1) with very
good PK properties. This compound dosed once daily at 30 mg/kg po showed
significant anti-inflammatory efficacy in HDM-induced allergic airway
inflammation in mice, reducing inflammatory cell influx in the BALF and total
IgE concentration in plasma, which correlated with decrease of chitinolytic
activity. Therapeutic efficacy of compound 7f in the clinically relevant
aeroallergen-induced acute asthma model in mice provides a rationale for
developing AMCase inhibitor for the treatment of asthma.
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
 |
 |
 |
|
Links
