Literature summary for 3.4.21.B10 extracted from

Sananes, A.; Cohen, I.; Shahar, A.; Hockla, A.; De Vita, E.; Miller, A.K.; Radisky, E.S.; Papo, N.
A potent, proteolysis-resistant inhibitor of kallikrein-related peptidase 6 (KLK6) for cancer therapy, developed by combinatorial engineering (2018), J. Biol. Chem., 293, 12663-12680 .

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Cloned(Commentary)

Cloned (Comment)	Organism
expresssion in Pichia pastoris	Homo sapiens

Crystallization (Commentary)

Crystallization (Comment)	Organism
crystal structures of the APPIWT/KLK6 and APPI-4M/KLK6 complexes reveal the structural and mechanistic bases for the improved KLK6 binding and proteolytic resistance of APPI-4M. APPI is the amyloid precursor protein Kunitz protease inhibitor domain. APPI-4M i.e. APPI(M17L/I18F/S19F/F34V)	Homo sapiens

Inhibitors

Inhibitors	Comment	Organism	Structure
amyloid precursor protein Kunitz protease inhibitor domain	combinatorial approach to engineering KLK6 inhibitors via flow cytometry-based screening of a yeast-displayed mutant library of the human amyloid precursor protein Kunitz protease inhibitor domain (APPI). On the basis of this screening, APPI(M17L/I18F/S19F/F34V) (APPI-4M) is generated, an APPI variant with a KLK6 inhibition constant (Ki) of 160 pM and a turnover time of 10 days. APPI-4M is a potent KLK6 inhibitor, displaying 146fold improved affinity and 13fold improved proteolytic stability compared with wild-type APPI (APPIWT). It is demonstrated that APPI-4M acts as a functional inhibitor in a cell-based model of KLK6-dependent breast cancer invasion	Homo sapiens
APPI-4M	combinatorial approach to engineering KLK6 inhibitors via flow cytometry-based screening of a yeast-displayed mutant library of the human amyloid precursor protein Kunitz protease inhibitor domain (APPI). On the basis of this screening, APPI(M17L/I18F/S19F/F34V) (APPI-4M) is generated, an APPI variant with a KLK6 inhibition constant (Ki) of 160 pM and a turnover time of 10 days. APPI-4M is a potent KLK6 inhibitor, displaying 146fold improved affinity and 13fold improved proteolytic stability compared with wild-type APPI (APPIWT). It is demonstrated that APPI-4M acts as a functional inhibitor in a cell-based model of KLK6-dependent breast cancer invasion	Homo sapiens

Organism

Organism	UniProt	Comment	Textmining
Homo sapiens	Q92876	-	-

Synonyms

Synonyms	Comment	Organism
kallikrein-related peptidase 6	-	Homo sapiens
KLK6	-	Homo sapiens

Ki Value [mM]

Ki Value [mM]	Ki Value maximum [mM]	Inhibitor	Comment	Organism	Structure
0.00000016	-	APPI-4M	pH and temperature not specified in the publication	Homo sapiens
0.00000224	-	amyloid precursor protein Kunitz protease inhibitor domain	pH and temperature not specified in the publication	Homo sapiens

Expression

Organism	Comment	Expression
Homo sapiens	highly up-regulated in several types of cancer, where its increased activity promotes cancer invasion and metastasis	up

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Release 2023.1 (January 2023)