PDBsum entry 5c7c

Apoptosis

PDB id: 5c7c

Contents

Protein chain

107 a.a.

Ligands

4YC

Metals

_ZN

Waters ×117

PDB id:

5c7c

Name:

Apoptosis

Title:

Fragment-based drug discovery targeting inhibitor of apoptosis proteins: compound 18

Structure:

E3 ubiquitin-protein ligase xiap. Chain: a. Fragment: residues 249-354. Synonym: baculoviral iap repeat-containing protein 4,iap-like protein,hilp,inhibitor of apoptosis protein 3,hiap3,x-linked inhibitor of apoptosis protein,x-linked iap. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: xiap, api3, birc4, iap3. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008.

Resolution:

2.32Å R-factor: 0.227 R-free: 0.286

Authors:

G.Chessari,I.M.Buck,J.E.H.Day,P.J.Day,A.Iqbal,C.N.Johnson,E.J.Lewis, V.Martins,D.Miller,M.Reader,D.C.Rees,S.J.Rich,E.Tamanini,M.Vitorino, G.A.Ward,P.A.Williams,G.Williams,N.E.Wilsher,A.J.-A.Woolford

Key ref:

G.Chessari et al. (2015). Fragment-Based Drug Discovery Targeting Inhibitor of Apoptosis Proteins: Discovery of a Non-Alanine Lead Series with Dual Activity Against cIAP1 and XIAP. J Med Chem, 58, 6574-6588. PubMed id: 26218264 DOI: 10.1021/acs.jmedchem.5b00706

Date:

24-Jun-15 Release date: 12-Aug-15

Protein chain

P98170  (XIAP_HUMAN) -  E3 ubiquitin-protein ligase XIAP from Homo sapiens

Seq: 497 a.a.

Struc: 107 a.a.*

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

Enzyme reactions

• Enzyme class: E.C.2.3.2.27 - RING-type E3 ubiquitin transferase.
• Reaction: S-ubiquitinyl-[E2 ubiquitin-conjugating enzyme]-L-cysteine + [acceptor protein]-L-lysine = [E2 ubiquitin-conjugating enzyme]-L-cysteine + N₆- ubiquitinyl-[acceptor protein]-L-lysine

DOI no: 10.1021/acs.jmedchem.5b00706

J Med Chem 58:6574-6588 (2015)

PubMed id: 26218264

Fragment-Based Drug Discovery Targeting Inhibitor of Apoptosis Proteins: Discovery of a Non-Alanine Lead Series with Dual Activity Against cIAP1 and XIAP.

G.Chessari, I.M.Buck, J.E.Day, P.J.Day, A.Iqbal, C.N.Johnson, E.J.Lewis, V.Martins, D.Miller, M.Reader, D.C.Rees, S.J.Rich, E.Tamanini, M.Vitorino, G.A.Ward, P.A.Williams, G.Williams, N.E.Wilsher, A.J.Woolford.

ABSTRACT

Inhibitor of apoptosis proteins (IAPs) are important regulators of apoptosis and pro-survival signaling pathways whose deregulation is often associated with tumor genesis and tumor growth. IAPs have been proposed as targets for anticancer therapy, and a number of peptidomimetic IAP antagonists have entered clinical trials. Using our fragment-based screening approach, we identified nonpeptidic fragments binding with millimolar affinities to both cellular inhibitor of apoptosis protein 1 (cIAP1) and X-linked inhibitor of apoptosis protein (XIAP). Structure-based hit optimization together with an analysis of protein-ligand electrostatic potential complementarity allowed us to significantly increase binding affinity of the starting hits. Subsequent optimization gave a potent nonalanine IAP antagonist structurally distinct from all IAP antagonists previously reported. The lead compound had activity in cell-based assays and in a mouse xenograft efficacy model and represents a highly promising start point for further optimization.