PDBsum entry 4kkd

Hydrolase

PDB id: 4kkd

Contents

Protein chains

390 a.a.

405 a.a.

Ligands

IMD

Waters ×201

PDB id:

4kkd

Name:

Hydrolase

Title:

The x-ray crystal structure of mannose-binding lectin-associated serine proteinase-3 reveals the structural basis for enzyme inactivity associated with the 3mc syndrome

Structure:

Mannan-binding lectin serine protease 1. Chain: a, b. Synonym: complement factor masp-3, complement-activating component of ra-reactive factor, mannose-binding lectin-associated serine protease 1, masp-1, mannose-binding protein-associated serine protease, ra- reactive factor serine protease p100, rarf, serine protease 5, mannan-binding lectin serine protease 1 heavy chain, mannan-binding lectin serine protease 1 light chain. Engineered: yes.

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: crarf, crarf1, masp1, prss5. Expressed in: escherichia coli. Expression_system_taxid: 562

Resolution:

2.60Å R-factor: 0.196 R-free: 0.260

Authors:

T.Yongqing,P.G.Wilmann,S.B.Reeve,T.H.Coetzer,A.I.Smith,J.C.Whisstock, R.N.Pike,L.C.Wijeyewickrema

Key ref:

T.Yongqing et al. (2013). The x-ray crystal structure of mannose-binding lectin-associated serine proteinase-3 reveals the structural basis for enzyme inactivity associated with the Carnevale, Mingarelli, Malpuech, and Michels (3MC) syndrome. J Biol Chem, 288, 22399-22407. PubMed id: 23792966 DOI: 10.1074/jbc.M113.483875

Date:

05-May-13 Release date: 03-Jul-13

Protein chain

P48740  (MASP1_HUMAN) -  Mannan-binding lectin serine protease 1 from Homo sapiens

Seq: 699 a.a.

Struc: 390 a.a.*

Protein chain

P48740  (MASP1_HUMAN) -  Mannan-binding lectin serine protease 1 from Homo sapiens

Seq: 699 a.a.

Struc: 405 a.a.*

* PDB and UniProt seqs differ at 332 residue positions (black crosses)

Enzyme reactions

• Enzyme class: Chains A, B: E.C.3.4.21.- - ?????

DOI no: 10.1074/jbc.M113.483875

J Biol Chem 288:22399-22407 (2013)

PubMed id: 23792966

The x-ray crystal structure of mannose-binding lectin-associated serine proteinase-3 reveals the structural basis for enzyme inactivity associated with the Carnevale, Mingarelli, Malpuech, and Michels (3MC) syndrome.

T.Yongqing, P.G.Wilmann, S.B.Reeve, T.H.Coetzer, A.I.Smith, J.C.Whisstock, R.N.Pike, L.C.Wijeyewickrema.

ABSTRACT

The mannose-binding lectin associated-protease-3 (MASP-3) is a member of the lectin pathway of the complement system, a key component of human innate and active immunity. Mutations in MASP-3 have recently been found to be associated with Carnevale, Mingarelli, Malpuech, and Michels (3MC) syndrome, a severe developmental disorder manifested by cleft palate, intellectual disability, and skeletal abnormalities. However, the molecular basis for MASP-3 function remains to be understood. Here we characterize the substrate specificity of MASP-3 by screening against a combinatorial peptide substrate library. Through this approach, we successfully identified a peptide substrate that was 20-fold more efficiently cleaved than any other identified to date. Furthermore, we demonstrated that mutant forms of the enzyme associated with 3MC syndrome were completely inactive against this substrate. To address the structural basis for this defect, we determined the 2.6-Å structure of the zymogen form of the G666E mutant of MASP-3. These data reveal that the mutation disrupts the active site and perturbs the position of the catalytic serine residue. Together, these insights into the function of MASP-3 reveal how a mutation in this enzyme causes it to be inactive and thus contribute to the 3MC syndrome.