3RM4

AMCase in complex with Compound 1

Summary for 3RM4

• Entry DOI: 10.2210/pdb3rm4/pdb
• Related: 3RM8 3RM9 3RME
• Descriptor: Acidic mammalian chitinase, 5-{4-[2-(4-bromophenoxy)ethyl]piperazin-1-yl}-4H-1,2,4-triazol-3-amine (3 entities in total)
• Functional Keywords: hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Secreted. Isoform 2: Cytoplasm. Isoform 3: Cytoplasm: Q9BZP6
• Total number of polymer chains: 2
• Total formula weight: 89141.23

Authors

Olland, A. (deposition date: 2011-04-20, release date: 2011-08-24, Last modification date: 2024-10-16)

Primary citation

Cole, D.C.,Olland, A.M.,Jacob, J.,Brooks, J.,Bursavich, M.G.,Czerwinski, R.,Declercq, C.,Johnson, M.,Joseph-McCarthy, D.,Ellingboe, J.W.,Lin, L.,Nowak, P.,Presman, E.,Strand, J.,Tam, A.,Williams, C.M.M.,Yao, S.,Tsao, D.H.H.,Fitz, L.J.
Identification and Characterization of Acidic Mammalian Chitinase Inhibitors
J.Med.Chem., 53:6122-6128, 2010

PubMed Abstract: Acidic mammalian chitinase (AMCase) is a member of the glycosyl hydrolase 18 family (EC 3.2.1.14) that has been implicated in the pathophysiology of allergic airway disease such as asthma. Small molecule inhibitors of AMCase were identified using a combination of high-throughput screening, fragment screening, and virtual screening techniques and characterized by enzyme inhibition and NMR and Biacore binding experiments. X-ray structures of the inhibitors in complex with AMCase revealed that the larger more potent HTS hits, e.g. 5-(4-(2-(4-bromophenoxy)ethyl)piperazine-1-yl)-1H-1,2,4-triazol-3-amine 1, spanned from the active site pocket to a hydrophobic pocket. Smaller fragments identified by FBS occupy both these pockets independently and suggest potential strategies for linking fragments. Compound 1 is a 200 nM AMCase inhibitor which reduced AMCase enzymatic activity in the bronchoalveolar lavage fluid in allergen-challenged mice after oral dosing.

PubMed: 20666458

Experimental method

X-RAY DIFFRACTION (1.9 Å)