Structural highlights
Function
[FURIN_HUMAN] Furin is likely to represent the ubiquitous endoprotease activity within constitutive secretory pathways and capable of cleavage at the RX(K/R)R consensus motif.[1]
Publication Abstract from PubMed
Proprotein convertases (PCs) represent highly selective serine proteases that activate their substrates upon proteolytic cleavage. Their inhibition is a promising strategy for the treatment of several pathologies including cancer, atherosclerosis, hypercholesterolaemia, and infectious diseases. Here, we present the first experimental complex of furin with a non-substrate-like small molecule inhibitor, and the X-ray structure of the enzyme complexed to the small molecule inhibitor 1 at 1.9 A resolution. Two molecules of inhibitor 1 were found to interact with furin. One is anchored at the S4 pocket of the enzyme and interferes directly with the conformation and function of the catalytic triade; the other molecule shows weaker binding and interacts with a distant, less conserved region of furin. The observed binding modes represent a new inhibition strategy of furin and imply the possibility to attain specificity among the PCs providing an innovative starting point of structure guided inhibitor development for furin.
Structural Studies Revealed Active Site Distortions of Human Furin by a Small Molecule Inhibitor.,Dahms SO, Jiao GS, Than ME ACS Chem Biol. 2017 Apr 17. doi: 10.1021/acschembio.6b01110. PMID:28402100[2]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Takahashi S, Kasai K, Hatsuzawa K, Kitamura N, Misumi Y, Ikehara Y, Murakami K, Nakayama K. A mutation of furin causes the lack of precursor-processing activity in human colon carcinoma LoVo cells. Biochem Biophys Res Commun. 1993 Sep 15;195(2):1019-26. PMID:7690548 doi:http://dx.doi.org/10.1006/bbrc.1993.2146
- ↑ Dahms SO, Jiao GS, Than ME. Structural Studies Revealed Active Site Distortions of Human Furin by a Small Molecule Inhibitor. ACS Chem Biol. 2017 Apr 17. doi: 10.1021/acschembio.6b01110. PMID:28402100 doi:http://dx.doi.org/10.1021/acschembio.6b01110
