4bfd

CRYSTAL STRUCTURE OF BACE-1 IN COMPLEX WITH CHEMICAL LIGANDCRYSTAL STRUCTURE OF BACE-1 IN COMPLEX WITH CHEMICAL LIGAND

Structural highlights

4bfd is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.3Å
Ligands:	, ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

BACE1_HUMAN Responsible for the proteolytic processing of the amyloid precursor protein (APP). Cleaves at the N-terminus of the A-beta peptide sequence, between residues 671 and 672 of APP, leads to the generation and extracellular release of beta-cleaved soluble APP, and a corresponding cell-associated C-terminal fragment which is later released by gamma-secretase.^[1] ^[2]

Publication Abstract from PubMed

A series of amides bearing a variety of amidine head groups was investigated as BACE1 inhibitors with respect to inhibitory activity in a BACE1 enzyme as well as a cell-based assay. Determination of their basicity as well as their properties as substrates of P-glycoprotein revealed that a 2-amino-1,3-oxazine head group would be a suitable starting point for further development of brain penetrating compounds for potential Alzheimer's disease treatment.

BACE1 inhibitors: A head group scan on a series of amides.,Woltering TJ, Wostl W, Hilpert H, Rogers-Evans M, Pinard E, Mayweg A, Gobel M, Banner DW, Benz J, Travagli M, Pollastrini M, Marconi G, Gabellieri E, Guba W, Mauser H, Andreini M, Jacobsen H, Power E, Narquizian R Bioorg Med Chem Lett. 2013 May 18. pii: S0960-894X(13)00585-4. doi:, 10.1016/j.bmcl.2013.05.003. PMID:23735744^[3]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Lin X, Koelsch G, Wu S, Downs D, Dashti A, Tang J. Human aspartic protease memapsin 2 cleaves the beta-secretase site of beta-amyloid precursor protein. Proc Natl Acad Sci U S A. 2000 Feb 15;97(4):1456-60. PMID:10677483
↑ Okada H, Zhang W, Peterhoff C, Hwang JC, Nixon RA, Ryu SH, Kim TW. Proteomic identification of sorting nexin 6 as a negative regulator of BACE1-mediated APP processing. FASEB J. 2010 Aug;24(8):2783-94. doi: 10.1096/fj.09-146357. Epub 2010 Mar 30. PMID:20354142 doi:10.1096/fj.09-146357
↑ Woltering TJ, Wostl W, Hilpert H, Rogers-Evans M, Pinard E, Mayweg A, Gobel M, Banner DW, Benz J, Travagli M, Pollastrini M, Marconi G, Gabellieri E, Guba W, Mauser H, Andreini M, Jacobsen H, Power E, Narquizian R. BACE1 inhibitors: A head group scan on a series of amides. Bioorg Med Chem Lett. 2013 May 18. pii: S0960-894X(13)00585-4. doi:, 10.1016/j.bmcl.2013.05.003. PMID:23735744 doi:10.1016/j.bmcl.2013.05.003

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OCA

[1] Lin X, Koelsch G, Wu S, Downs D, Dashti A, Tang J. Human aspartic protease memapsin 2 cleaves the beta-secretase site of beta-amyloid precursor protein. Proc Natl Acad Sci U S A. 2000 Feb 15;97(4):1456-60. PMID:10677483

[2] Okada H, Zhang W, Peterhoff C, Hwang JC, Nixon RA, Ryu SH, Kim TW. Proteomic identification of sorting nexin 6 as a negative regulator of BACE1-mediated APP processing. FASEB J. 2010 Aug;24(8):2783-94. doi: 10.1096/fj.09-146357. Epub 2010 Mar 30. PMID:20354142 doi:10.1096/fj.09-146357

[3] Woltering TJ, Wostl W, Hilpert H, Rogers-Evans M, Pinard E, Mayweg A, Gobel M, Banner DW, Benz J, Travagli M, Pollastrini M, Marconi G, Gabellieri E, Guba W, Mauser H, Andreini M, Jacobsen H, Power E, Narquizian R. BACE1 inhibitors: A head group scan on a series of amides. Bioorg Med Chem Lett. 2013 May 18. pii: S0960-894X(13)00585-4. doi:, 10.1016/j.bmcl.2013.05.003. PMID:23735744 doi:10.1016/j.bmcl.2013.05.003

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