4K8Y

Atomic resolution crystal structures of Kallikrein-Related Peptidase 4 complexed with Sunflower Trypsin Inhibitor (SFTI-1)

Summary for 4K8Y

• Entry DOI: 10.2210/pdb4k8y/pdb
• Related: 1SFI 2bdg 2bdh 2bdi 4K1E 4KEL 4KGA
• Related PRD ID: PRD_001097
• Descriptor: Kallikrein-4, Trypsin inhibitor 1 (3 entities in total)
• Functional Keywords: bowman-birk inhibitor, protease, protease inhibitor, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Homo sapiens (human); More
• Cellular location: Secreted: Q9Y5K2
• Total number of polymer chains: 2
• Total formula weight: 25461.84

Authors

Ilyichova, O.V.,Swedberg, J.E.,de Veer, S.J.,Sit, K.C.,Harris, J.M.,Buckle, A.M. (deposition date: 2013-04-19, release date: 2014-04-23, Last modification date: 2023-11-08)

Primary citation

Riley, B.T.,Ilyichova, O.,Costa, M.G.S.,Porebski, B.T.,de Veer, S.J.,Swedberg, J.E.,Kass, I.,Harris, J.M.,Hoke, D.E.,Buckle, A.M.
Direct and indirect mechanisms of KLK4 inhibition revealed by structure and dynamics
Sci Rep, 6:35385-35385, 2016

PubMed Abstract: The kallikrein-related peptidase (KLK) family of proteases is involved in many aspects of human health and disease. One member of this family, KLK4, has been implicated in cancer development and metastasis. Understanding mechanisms of inactivation are critical to developing selective KLK4 inhibitors. We have determined the X-ray crystal structures of KLK4 in complex with both sunflower trypsin inhibitor-1 (SFTI-1) and a rationally designed SFTI-1 derivative to atomic (~1 Å) resolution, as well as with bound nickel. These structures offer a structural rationalization for the potency and selectivity of these inhibitors, and together with MD simulation and computational analysis, reveal a dynamic pathway between the metal binding exosite and the active site, providing key details of a previously proposed allosteric mode of inhibition. Collectively, this work provides insight into both direct and indirect mechanisms of inhibition for KLK4 that have broad implications for the enzymology of the serine protease superfamily, and may potentially be exploited for the design of therapeutic inhibitors.

PubMed: 27767076
DOI: 10.1038/srep35385

Experimental method

X-RAY DIFFRACTION (1 Å)