We apologize for Proteopedia being slow to respond. For the past two years, a new implementation of Proteopedia has been being built. Soon, it will replace this 18-year old system. All existing content will be moved to the new system at a date that will be announced here.

5zfi

From Proteopedia

Jump to: navigation, search

Mouse kallikrein 7 in complex with 6-benzyl-1,4-diazepan-7-one derivative

Structural highlights

5zfi is a 1 chain structure with sequence from Mus musculus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 1.8Å
Ligands:	,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

KLK7_MOUSE May catalyze the degradation of intercellular cohesive structures in the cornified layer of the skin in the continuous shedding of cells from the skin surface. Specific for amino acid residues with aromatic side chains in the P1 position. Cleaves insulin A chain at '14-Tyr-|-Gln-15' and insulin B chain at '6-Leu-|-Cys-7', '16-Tyr-|-Leu-17', '25-Phe-|-Tyr-26' and '26-Tyr-|-Thr-27'. Could play a role in the activation of precursors to inflammatory cytokines.

Publication Abstract from PubMed

A series of 1,3,6-trisubstituted 1,4-diazepan-7-ones were prepared as kallikrein 7 (KLK7, stratum corneum chymotryptic enzyme) inhibitors. Previously reported compounds 1-3 were potent human KLK7 inhibitors; however, they did not exhibit inhibitory activity against mouse KLK7. Comparison of the human and mouse KLK7 structures reveals the cause of this species differences; therefore, compounds that could inhibit both KLK7s were designed, synthesized, and evaluated. Through this structure-based drug design, compound 22g was identified as an inhibitor against human and mouse KLK7, and only one of the enantiomers, (-)-22g, exhibited potent inhibitory activity. Furthermore, the crystal structure of mouse KLK7 complexed with 22g enabled the elucidation of structure-activity relationships and justified 22g as a valuable compound to overcome the species differences.

Structure-based drug design to overcome species differences in kallikrein 7 inhibition of 1,3,6-trisubstituted 1,4-diazepan-7-ones.,Murafuji H, Sugawara H, Goto M, Oyama Y, Sakai H, Imajo S, Tomoo T, Muto T Bioorg Med Chem. 2018 Jul 23;26(12):3639-3653. doi: 10.1016/j.bmc.2018.05.044., Epub 2018 May 26. PMID:29884582^[1]

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

References

↑ Murafuji H, Sugawara H, Goto M, Oyama Y, Sakai H, Imajo S, Tomoo T, Muto T. Structure-based drug design to overcome species differences in kallikrein 7 inhibition of 1,3,6-trisubstituted 1,4-diazepan-7-ones. Bioorg Med Chem. 2018 Jul 23;26(12):3639-3653. doi: 10.1016/j.bmc.2018.05.044., Epub 2018 May 26. PMID:29884582 doi:http://dx.doi.org/10.1016/j.bmc.2018.05.044