PDBsum entry: 1hkm

Hydrolase

PDB id: 1hkm

Contents

Protein chain

365 a.a. *

Ligands

NAA-NAA-ALI

Waters ×52

* Residue conservation analysis

PDB id:

1hkm

Name:

Hydrolase

Title:

High resolution crystal structure of human chitinase in complex with demethylallosamidin

Structure:

Chitotriosidase. Chain: a. Synonym: endochitinase. Other_details: glucose allosamidin b

Source:

Homo sapiens. Human. Organism_taxid: 9606. Cell: macrophages

Resolution:

2.55Å R-factor: 0.213 R-free: 0.255

Authors:

F.V.Rao,D.R.Houston,R.G.Boot,J.M.F.G.Aerts,S.Sakuda, D.M.F.Van Aalten

Key ref:

F.V.Rao et al. (2003). Crystal structures of allosamidin derivatives in complex with human macrophage chitinase. J Biol Chem, 278, 20110-20116. PubMed id: 12639956 DOI: 10.1074/jbc.M300362200

Date:

10-Mar-03 Release date: 11-Mar-04

Protein chain

Q13231  (CHIT1_HUMAN) -  Chitotriosidase-1

Seq: 466 a.a.

Struc: 365 a.a.*

* PDB and UniProt seqs differ at 1 residue position (black cross)

Enzyme reactions

• 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.

 Gene Ontology (GO) functional annotation 

• Biological process: carbohydrate metabolic process (2 terms)
• Biochemical function: catalytic activity (4 terms)

DOI no: 10.1074/jbc.M300362200

J Biol Chem 278:20110-20116 (2003)

PubMed id: 12639956

Crystal structures of allosamidin derivatives in complex with human macrophage chitinase.

F.V.Rao, D.R.Houston, R.G.Boot, J.M.Aerts, S.Sakuda, D.M.van Aalten.

ABSTRACT

The pseudotrisaccharide allosamidin is a potent family 18 chitinase inhibitor with demonstrated biological activity against insects, fungi, and the Plasmodium falciparum life cycle. The synthesis and biological properties of several derivatives have been reported. The structural interactions of allosamidin with several family 18 chitinases have been determined by x-ray crystallography previously. Here, a high resolution structure of chitotriosidase, the human macrophage chitinase, in complex with allosamidin is presented. In addition, complexes of the allosamidin derivatives demethylallosamidin, methylallosamidin, and glucoallosamidin B are described, together with their inhibitory properties. Similar to other chitinases, inhibition of the human chitinase by allosamidin derivatives lacking a methyl group is 10-fold stronger, and smaller effects are observed for the methyl and C3 epimer derivatives. The structures explain the effects on inhibition in terms of altered hydrogen bonding and hydrophobic interactions, together with displaced water molecules. The data reported here represent a first step toward structure-based design of specific allosamidin derivatives.

Selected figure(s)

Figure 3.
FIG. 3. Complexes with allosamidin derivatives. Stereo images of the final structures of the human chitinase in complex with allosamidin and its derivatives are shown. Side chains interacting with the allosamidins (also indicated in Fig. 2) are shown in a sticks representation. The allosamidins are shown as a sticks model with orange carbons. Water molecules involved in allosamidin hydrogen bonds are shown as red spheres. Hydrogen bonds are shown as dotted green lines and are listed in Table IV. The unbiased F[o] - F[c], [calc] maps before inclusion of models for the inhibitors in the refinement are shown in magenta, contoured at 2.25 .

Figure 4.
FIG. 4. Sequence conservation in the active site. Stereo image of the molecular surfaces calculated from HCHT in the HCHT·ALLO complex and hevamine in the hevamine·ALLO complex (18) is shown. Blue surface corresponds to conserved residues (Fig. 2), which are also shown as a sticks model. ALLO is shown as a sticks model with green carbons. The / domain, absent in hevamine, is indicated in HCHT.

The above figures are reprinted by permission from the ASBMB: J Biol Chem (2003, 278, 20110-20116) copyright 2003.

Figures were selected by an automated process.