1TFT

NMR Structure of an Antagonists of the XIAP-Caspase-9 Interaction Complexed to the BIR3 domain of XIAP

PDB DOI: https://doi.org/10.2210/pdb1TFT/pdb

Classification: APOPTOSIS
Organism(s): Homo sapiens
Expression System: Escherichia coli
Mutation(s): No

Deposited: 2004-05-27 Released: 2005-05-03
Deposition Author(s): Oost, T.K., Sun, C., Armstrong, R.C., Al-Assaad, A.S., Betz, S.F., Deckwerth, T.L., Elmore, S.W., Meadows, R.P., Olejniczak, E.T., Oleksijew, A.K., Oltersdorf, T., Rosenberg, S.H., Shoemaker, A.R., Zou, H., Fesik, S.W.

Experimental Data Snapshot

Method: SOLUTION NMR
Conformers Submitted: 1

wwPDB Validation 3D Report Full Report

This is version 1.3 of the entry. See complete history.

Literature

Discovery of potent antagonists of the antiapoptotic protein XIAP for the treatment of cancer.

Oost, T.K., Sun, C., Armstrong, R.C., Al-Assaad, A.S., Betz, S.F., Deckwerth, T.L., Ding, H., Elmore, S.W., Meadows, R.P., Olejniczak, E.T., Oleksijew, A.K., Oltersdorf, T., Rosenberg, S.H., Shoemaker, A.R., Tomaselli, K.J., Zou, H., Fesik, S.W.

(2004) J Med Chem 47: 4417-4426

PubMed: 15317454 Search on PubMed
DOI: https://doi.org/10.1021/jm040037k
Primary Citation of Related Structures:
1TFQ, 1TFT

PubMed Abstract:
Inhibitor of apoptosis (IAP) proteins are overexpressed in many cancers and have been implicated in tumor growth, pathogenesis, and resistance to chemo- or radiotherapy. On the basis of the NMR structure of a SMAC peptide complexed with the BIR3 domain of X-linked IAP (XIAP), a novel series of XIAP antagonists was discovered. The most potent compounds in this series bind to the baculovirus IAP repeat 3 (BIR3) domain of XIAP with single-digit nanomolar affinity and promote cell death in several human cancer cell lines. In a MDA-MB-231 breast cancer mouse xenograft model, these XIAP antagonists inhibited the growth of tumors. Close structural analogues that showed only weak binding to the XIAP-BIR3 domain were inactive in the cellular assays and showed only marginal in vivo activity. Our results are consistent with a mechanism in which ligands for the BIR3 domain of XIAP induce apoptosis by freeing up caspases. The present study validates the BIR3 domain of XIAP as a target and supports the use of small molecule XIAP antagonists as a potential therapy for cancers that overexpress XIAP.

Organizational Affiliation

Cancer Research, Global Pharmaceutical Research and Development, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, Illinois 60064, USA. thorsten.oost@abbott.com

Macromolecule Content

Total Structure Weight: 14.03 kDa
Atom Count: 985
Modelled Residue Count: 117
Deposited Residue Count: 117
Unique protein chains: 1

Macromolecules

Find similar proteins by:

(by identity cutoff) | 3D Structure

Entity ID: 1
Molecule	Chains	Sequence Length	Organism	Details	Image
Baculoviral IAP repeat-containing protein 4	A	117	Homo sapiens	Mutation(s): 0 Gene Names: BIRC4, API3, IAP3, XIAP
UniProt & NIH Common Fund Data Resources
Find proteins for P98170 (Homo sapiens) Explore P98170 Go to UniProtKB: P98170
PHAROS: P98170 GTEx: ENSG00000101966
Entity Groups
Sequence Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt Group	P98170
Sequence Annotations Expand
Reference Sequence

Small Molecules

Ligands 2 Unique
ID	Chains	Name / Formula / InChI Key	2D Diagram	3D Interactions
997 Query on 997 Download Ideal Coordinates CCD File SDF format, chain C [auth A] MOL2 format, chain C [auth A]	C [auth A]	1-[3,3-DIMETHYL-2-(2-METHYLAMINO-PROPIONYLAMINO)-BUTYRYL]-4-PHENOXY-PYRROLIDINE-2-CARBOXYLIC ACID(1,2,3,4-TETRAHYDRO-NAPHTHALEN-1-YL)-AMIDE C₃₁ H₄₂ N₄ O₄ QKPXPZYQPBWDHS-MCJAPYMPSA-N		Interactions Focus chain C [auth A]
ZN Query on ZN Download Ideal Coordinates CCD File SDF format, chain B [auth A] MOL2 format, chain B [auth A]	B [auth A]	ZINC ION Zn PTFCDOFLOPIGGS-UHFFFAOYSA-N		Interactions Focus chain B [auth A]