PDBsum entry 1dfp

Serine protease

PDB id: 1dfp

Contents

Protein chain

228 a.a. *

Ligands

DFP ×2

Waters ×262

* Residue conservation analysis

PDB id:

1dfp

Name:

Serine protease

Title:

Factor d inhibited by diisopropyl fluorophosphate

Structure:

Factor d. Chain: a, b. Other_details: diisopropyl phosphoryl group linked to serine 195

Source:

Homo sapiens. Human. Organism_taxid: 9606. Other_details: isolated from a patient with fanconi's syndrome

Resolution:

2.40Å R-factor: 0.148 R-free: 0.228

Authors:

L.B.Cole,N.Chu,J.M.Kilpatrick,J.E.Volanakis,S.V.L.Narayana,Y.S.Babu

Key ref:

L.B.Cole et al. (1997). Structure of diisopropyl fluorophosphate-inhibited factor D. Acta Crystallogr D Biol Crystallogr, 53, 143-150. PubMed id: 15299948 DOI: 10.1107/S0907444996012991

Date:

18-Feb-97 Release date: 25-Feb-98

Protein chains

P00746  (CFAD_HUMAN) -  Complement factor D from Homo sapiens

Seq: 253 a.a.

Struc: 228 a.a.

Enzyme reactions

• Enzyme class: E.C.3.4.21.46 - complement factor D.
• Reaction: Cleaves component factor B (Arg-|-Lys) when in complex with C3b or with cobra venom factor (CVF).

DOI no: 10.1107/S0907444996012991

Acta Crystallogr D Biol Crystallogr 53:143-150 (1997)

PubMed id: 15299948

Structure of diisopropyl fluorophosphate-inhibited factor D.

L.B.Cole, N.Chu, J.M.Kilpatrick, J.E.Volanakis, S.V.Narayana, Y.S.Babu.

ABSTRACT

Factor D (D) is a serine protease, crucial for the activation of the alternative complement pathway. Only a limited number of general serine protease inhibitors are known to inhibit D, most of which covalently bind to the serine hydroxyl of the catalytic triad. The structure of the first enzyme:inhibitor covalent adduct of D with diisopropyl fluorophosphate (DIP:D) to a resolution of 2.4 A is described. The inhibited enzyme is similar in overall structure to the native enzyme and to trypsin, yet exhibits notable differences in the active site. One region of the active site is conserved between D and trypsin with respect to amino-acid sequence and to conformation. Another reflects the amino-acid substitutions and conformational flexibility between these enzymes. The active-site histidine residue is observed in the gauche+ conformation, not the normal gauche- orientation seen in the classic catalytic triad arrangement required for enzymatic activity in serine proteases. Comparisons of the active sites between native D, the DIP:D adduct, and DIP-inhibited trypsin have provided fundamental insights currently being employed in the design of novel small-molecule pharmaceutical agents capable of modulating the alternative complement pathway.

Selected figure(s)

Figure 2.
Fig. 2. Stereo ribbon diagram of the superposed structures of DIPB (yellow), FADB (magenta), and trypsin, of 4PTP (blue). All stereodiagrams were created uti­ lizing the Insight II molecular modeling system.

Figure 3.
Fig. 3. Stereo Cu drawing of the DIPA (red) and DIPB (yellow) monomers. The DIP moieties are shown in the active sites, and colored by atom types.

The above figures are reprinted by permission from the IUCr: Acta Crystallogr D Biol Crystallogr (1997, 53, 143-150) copyright 1997.

Figures were selected by an automated process.