Crystal structure of human cathepsin V.
Cathepsin V is a lysosomal cysteine protease that is expressed in the thymus, testis and corneal epithelium. We have determined the 1.6 A resolution crystal structure of human cathepsin V associated with an irreversible vinyl sulfone inhibitor. The fold of this enzyme is similar to the fold adopted by other members of the papain superfamily of cysteine proteases. This study provides a framework for understanding the structural basis for cathepsin V's activity and will aid in the design of inhibitors of this enzyme. A comparison of cathepsin V's active site with the active sites of related proteases revealed a number of differences, especially in the S2 and S3 subsites, that could be exploited in identifying specific cathepsin V inhibitors or in identifying inhibitors of other cysteine proteases that would be selective against cathepsin V.
Somoza
J R
JR
Axys Pharmaceuticals, Inc., 385 Oyster Point Boulevard, Suite 1, South San Francisco, California 94080, USA. john_somoza@axyspharm.com
Zhan
H
H
Bowman
K K
KK
Yu
L
L
Mortara
K D
KD
Palmer
J T
JT
Clark
J M
JM
McGrath
M E
ME
D001665:Binding Sites; D020134:Catalytic Domain; D002403:Cathepsins / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000235:genetics / Q000302:isolation & purification; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D003546:Cysteine Endopeptidases / Q000737:chemistry* / Q000235:genetics / Q000302:isolation & purification; D015853:Cysteine Proteinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry; D006801:Humans; D008958:Models, Molecular; D016297:Mutagenesis, Site-Directed; D010649:Phenylalanine / Q000031:analogs & derivatives; D010879:Piperazines / Q000138:chemical synthesis / Q000737:chemistry; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D013450:Sulfones / Q000138:chemical synthesis / Q000737:chemistry; D014105:Tosyl Compounds
D015853:Cysteine Proteinase Inhibitors; D010879:Piperazines; D013450:Sulfones; D014105:Tosyl Compounds; C487484:N-pip-phenylalanine-homophenylalanine-vinyl sulfone phenyl; D010649:Phenylalanine; D002403:Cathepsins; D003546:Cysteine Endopeptidases; C117627:CTSV protein, human