Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TTW26OG)

• DTT Name: Endoplasmic reticulum chaperone BiP (HSPA5)
• Synonyms: Immunoglobulin heavy chainbinding protein; Immunoglobulin heavy chain-binding protein; Heat shock protein family A member 5; Heat shock protein 70 family protein 5; Heat shock 70 kDa protein 5; HSP70 family protein 5; GRP78; GRP-78; Endoplasmic reticulum lumenal Ca(2+)binding protein grp78; Binding-immunoglobulin protein; BiP; 78 kDa glucose-regulated protein
• Gene Name: HSPA5
• DTT Type: Clinical trial target; [1]
• BioChemical Class: Acid anhydride hydrolase
• UniProt ID: BIP_HUMAN
• TTD ID: T77594
• EC Number: EC 3.6.4.10
• Sequence:
  MKLSLVAAMLLLLSAARAEEEDKKEDVGTVVGIDLGTTYSCVGVFKNGRVEIIANDQGNR
  ITPSYVAFTPEGERLIGDAAKNQLTSNPENTVFDAKRLIGRTWNDPSVQQDIKFLPFKVV
  EKKTKPYIQVDIGGGQTKTFAPEEISAMVLTKMKETAEAYLGKKVTHAVVTVPAYFNDAQ
  RQATKDAGTIAGLNVMRIINEPTAAAIAYGLDKREGEKNILVFDLGGGTFDVSLLTIDNG
  VFEVVATNGDTHLGGEDFDQRVMEHFIKLYKKKTGKDVRKDNRAVQKLRREVEKAKRALS
  SQHQARIEIESFYEGEDFSETLTRAKFEELNMDLFRSTMKPVQKVLEDSDLKKSDIDEIV
  LVGGSTRIPKIQQLVKEFFNGKEPSRGINPDEAVAYGAAVQAGVLSGDQDTGDLVLLDVC
  PLTLGIETVGGVMTKLIPRNTVVPTKKSQIFSTASDNQPTVTIKVYEGERPLTKDNHLLG
  TFDLTGIPPAPRGVPQIEVTFEIDVNGILRVTAEDKGTGNKNKITITNDQNRLTPEEIER
  MVNDAEKFAEEDKKLKERIDTRNELESYAYSLKNQIGDKEKLGGKLSSEDKETMEKAVEE
  KIEWLESHQDADIEDFKAKKKELEEIVQPIISKLYGSAGPPPTGEEDTAEKDEL
• Function: Involved in the correct folding of proteins and degradation of misfolded proteins via its interaction with DNAJC10/ERdj5, probably to facilitate the release of DNAJC10/ERdj5 from its substrate. Acts as a key repressor of the ERN1/IRE1-mediated unfolded protein response (UPR). In the unstressed endoplasmic reticulum, recruited by DNAJB9/ERdj4 to the luminal region of ERN1/IRE1, leading to disrupt the dimerization of ERN1/IRE1, thereby inactivating ERN1/IRE1. Accumulation of misfolded protein in the endoplasmic reticulum causes release of HSPA5/BiP from ERN1/IRE1, allowing homodimerization and subsequent activation of ERN1/IRE1. Plays an auxiliary role in post-translational transport of small presecretory proteins across endoplasmic reticulum (ER). May function as an allosteric modulator for SEC61 channel-forming translocon complex, likely cooperating with SEC62 to enable the productive insertion of these precursors into SEC61 channel. Appears to specifically regulate translocation of precursors having inhibitory residues in their mature region that weaken channel gating. Endoplasmic reticulum chaperone that plays a key role in protein folding and quality control in the endoplasmic reticulum lumen.
• KEGG Pathway:
  Protein export (hsa03060)
  Protein processing in endoplasmic reticulum (hsa04141)
  Antigen processing and presentation (hsa04612)
  Thyroid hormone synthesis (hsa04918)
  Prion diseases (hsa05020)
• Reactome Pathway:
  Regulation of HSF1-mediated heat shock response (R-HSA-3371453)
  Platelet degranulation (R-HSA-114608)

Molecular Interaction Atlas (MIA) of This DTT

3 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
IT-139	DMBPV9W	Solid tumour/cancer	2A00-2F9Z	Phase 1	[1]
NKP-1339	DM5AWK1	Solid tumour/cancer	2A00-2F9Z	Phase 1	[1]
SAM-6	DMDHQYA	Melanoma	2C30	Phase 1	[2]

Molecular Expression Atlas (MEA) of This DTT

Disease Name	ICD 11	Studied Tissue	p-value	Fold-Change	Z-score
Melanoma	2C82	Skin	7.97E-01	0.09	0.16

References

• [1] NKP-1339, a first-in-class anticancer drug showing mild side effects and activity in patients suffering from advanced refractory cancer. BMC Pharmacol Toxicol. 2012; 13(Suppl 1): A82.
• [2] A new tumor-specific variant of GRP78 as target for antibody-based therapy. Lab Invest. 2008 Apr;88(4):375-86.