PDBsum entry 5hcd

Immune system

PDB id: 5hcd

Contents

Protein chains

647 a.a.

981 a.a.

148 a.a.

49 a.a.

Ligands

NAG-NAG

CYS

PDB id:

5hcd

Name:

Immune system

Title:

Ternary complex of human complement c5 with ornithodoros moubata omci and rhipicephalus microplus raci2

Structure:

Complement c5. Chain: b. Fragment: unp residues 19-674. Synonym: c3 and pzp-like alpha-2-macroglobulin domain-containing protein 4. Other_details: chains a and b are the product of a single gene that is processed into two chains that remain covalently linked via a disulphide.. Complement c5.

Source:

Homo sapiens. Human. Organism_taxid: 9606. Ornithodoros moubata. Soft tick. Organism_taxid: 6938. Gene: ci. Expressed in: kluyveromyces lactis. Expression_system_taxid: 28985.

Resolution:

2.98Å R-factor: 0.259 R-free: 0.282

Authors:

M.M.Jore,S.Johnson,S.M.Lea

Key ref:

M.M.Jore et al. (2016). Structural basis for therapeutic inhibition of complement C5. Nat Struct Biol, 23, 378-386. PubMed id: 27018802 DOI: 10.1038/nsmb.3196

Date:

04-Jan-16 Release date: 30-Mar-16

Protein chain

P01031  (CO5_HUMAN) -  Complement C5 from Homo sapiens

Seq: 1676 a.a.

Struc: 647 a.a.

Protein chain

P01031  (CO5_HUMAN) -  Complement C5 from Homo sapiens

Seq: 1676 a.a.

Struc: 981 a.a.

Protein chain

Q5YD59  (C5I_ORNMO) -  Complement inhibitor from Ornithodoros moubata

Seq: 168 a.a.

Struc: 148 a.a.*

Protein chain

A0A158RFT4  (C5I2_RHIMP) -  Complement inhibitor RaCI2 from Rhipicephalus microplus

Seq: 98 a.a.

Struc: 49 a.a.

* PDB and UniProt seqs differ at 2 residue positions (black crosses)

DOI no: 10.1038/nsmb.3196

Nat Struct Biol 23:378-386 (2016)

PubMed id: 27018802

Structural basis for therapeutic inhibition of complement C5.

M.M.Jore, S.Johnson, D.Sheppard, N.M.Barber, Y.I.Li, M.A.Nunn, H.Elmlund, S.M.Lea.

ABSTRACT

Activation of complement C5 generates the potent anaphylatoxin C5a and leads to pathogen lysis, inflammation and cell damage. The therapeutic potential of C5 inhibition has been demonstrated by eculizumab, one of the world's most expensive drugs. However, the mechanism of C5 activation by C5 convertases remains elusive, thus limiting development of therapeutics. Here we identify and characterize a new protein family of tick-derived C5 inhibitors. Structures of C5 in complex with the new inhibitors, the phase I and phase II inhibitor OmCI, or an eculizumab Fab reveal three distinct binding sites on C5 that all prevent activation of C5. The positions of the inhibitor-binding sites and the ability of all three C5-inhibitor complexes to competitively inhibit the C5 convertase conflict with earlier steric-inhibition models, thus suggesting that a priming event is needed for activation.