PDBsum entry 1x9o

Hydrolase

PDB id: 1x9o

Contents

Protein chain

242 a.a.

Ligands

_PC

Metals

_ZN ×2

Waters ×1

Theoretical model

PDB id:

1x9o

Name:

Hydrolase

Title:

A model of the acid sphingomyelinase phosphoesterase domain

Structure:

Sphingomyelin phosphodiesterase. Chain: a. Fragment: phosphoesterase domain. Synonym: acid sphingomyelinase, asmase. Ec: 3.1.4.12

Source:

Homo sapiens. Human

Authors:

M.Seto,M.Whitlow,M.A.Mccarrick,S.Srinivasan,R.Pagila,Y.Zhu, R.Mintzer,D.Light,A.Johns,J.A.Meurer-Ogden

Key ref:

M.Seto et al. (2004). A model of the acid sphingomyelinase phosphoesterase domain based on its remote structural homolog purple acid phosphatase. Protein Sci, 13, 3172-3186. PubMed id: 15557261 DOI: 10.1110/ps.04966204

Date:

23-Aug-04 Release date: 14-Dec-04

Protein chain

P17405  (ASM_HUMAN) -  Sphingomyelin phosphodiesterase from Homo sapiens

Seq: 631 a.a.

Struc: 243 a.a.*

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

DOI no: 10.1110/ps.04966204

Protein Sci 13:3172-3186 (2004)

PubMed id: 15557261

A model of the acid sphingomyelinase phosphoesterase domain based on its remote structural homolog purple acid phosphatase.

M.Seto, M.Whitlow, M.A.McCarrick, S.Srinivasan, Y.Zhu, R.Pagila, R.Mintzer, D.Light, A.Johns, J.A.Meurer-Ogden.

ABSTRACT

Sequence profile and fold recognition methods identified mammalian purple acid phosphatase (PAP), a member of a dimetal-containing phosphoesterase (DMP) family, as a remote homolog of human acid sphingomyelinase (ASM). A model of the phosphoesterase domain of ASM was built based on its predicted secondary structure and the metal-coordinating residues of PAP. Due to the low sequence identity between ASM and PAP (approximately 15%), the highest degree of confidence in the model resides in the metal-binding motifs. The ASM model predicts residues Asp 206, Asp 278, Asn 318, His 425, and His 457 to be dimetal coordinating. A putative orientation for the phosphorylcholine head group of the ASM substrate, sphingomyelin (SM), was made based on the predicted catalysis of the phosphorus-oxygen bond in the active site of ASM and on a structural comparison of the PAP-phosphate complex to the C-reactive protein-phosphorylcholine complex. These complexes revealed similar spatial interactions between the metal-coordinating residues, the metals, and the phosphate groups, suggesting a putative orientation for the head group in ASM consistent with the mechanism considerations. A conserved sequence motif in ASM, NX3CX3N, was identified (Asn 381 to Asn 389) and is predicted to interact with the choline amine moiety in SM. The resulting ASM model suggests that the enzyme uses an SN2-type catalytic mechanism to hydrolyze SM, similar to other DMPs. His 319 in ASM is predicted to protonate the ceramide-leaving group in the catalysis of SM. The putative functional roles of several ASM Niemann-Pick missense mutations, located in the predicted phosphoesterase domain, are discussed in context to the model.

Selected figure(s)

Figure 3.
Figure 3. Secondary structure rendering of the model of the human ASM phosphodiesterase domain. Secondary structures are indicated with red barrels ( -helices) and green arrows ( -sheets). The amino and carboxyl termini of the domain are labeled with "N" and "C," respectively. The dimetal center, indicated with a red arrow, is located within the pseudo twofold symmetry axis of this domain. The highest confidence region, consisting of the side chains of five predicted conserved metal-coordinating residues (D206, D278, N318, H425, and H457) are shown in red. The metal ions are indicated with pink spheres. The 30-residue insertion is indicated with a black arrow. (A) The side chains of the conserved residues with respect to the dimetal center are shown in purple: N381 and N389 from the NX[3]CX[3]N motif; Asp 210-Tyr 213 and His 282 from the cluster of hydrophilic/aromatic residues; and C250 and D251 from the CD dipeptide. (B) The side chains of the Niemann-Pick mutation residues are indicated in blue in context to the dimetal center: M382, N383, and W391 in or near the NX[3]CX[3]N motif; H319 in MM3; and L302, P371, and H421, predicted to lie outside of the dimetal center.

Figure 5.
Figure 5. Proposed catalytic mechanism for the hydrolysis of phosphodi-esters by ASM. The active site region of human ASM is displayed with the metal-coordinating residues. Zinc atoms are indicated in red. Phosphate is indicated in green. The bridging hydroxide ion is indicated in blue.

The above figures are reprinted by permission from the Protein Society: Protein Sci (2004, 13, 3172-3186) copyright 2004.

Figures were selected by an automated process.