PMID- 10022822
OWN - NLM
STAT- MEDLINE
DCOM- 19990426
LR  - 20190816
IS  - 0261-4189 (Print)
IS  - 0261-4189 (Linking)
VI  - 18
IP  - 4
DP  - 1999 Feb 15
TI  - Crystal structure of MHC class II-associated p41 Ii fragment bound to cathepsin L
      reveals the structural basis for differentiation between cathepsins L and S.
PG  - 793-803
AB  - The lysosomal cysteine proteases cathepsins S and L play crucial roles in the
      degradation of the invariant chain during maturation of MHC class II molecules
      and antigen processing. The p41 form of the invariant chain includes a fragment
      which specifically inhibits cathepsin L but not S. The crystal structure of the
      p41 fragment, a homologue of the thyroglobulin type-1 domains, has been
      determined at 2.0 A resolution in complex with cathepsin L. The structure of the 
      p41 fragment demonstrates a novel fold, consisting of two subdomains, each
      stabilized by disulfide bridges. The first subdomain is an
      alpha-helix-beta-strand arrangement, whereas the second subdomain has a
      predominantly beta-strand arrangement. The wedge shape and three-loop arrangement
      of the p41 fragment bound to the active site cleft of cathepsin L are reminiscent
      of the inhibitory edge of cystatins, thus demonstrating the first example of
      convergent evolution observed in cysteine protease inhibitors. However, the
      different fold of the p41 fragment results in additional contacts with the top of
      the R-domain of the enzymes, which defines the specificity-determining S2 and S1'
      substrate-binding sites. This enables inhibitors based on the thyroglobulin
      type-1 domain fold, in contrast to the rather non-selective cystatins, to exhibit
      specificity for their target enzymes.
FAU - Guncar, G
AU  - Guncar G
AD  - Department of Biochemistry and Molecular Biology, Jozcaronef Stefan Institute,
      Jamova 39, SLO-1000 Ljubljana, Slovenia.
FAU - Pungercic, G
AU  - Pungercic G
FAU - Klemencic, I
AU  - Klemencic I
FAU - Turk, V
AU  - Turk V
FAU - Turk, D
AU  - Turk D
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - EMBO J
JT  - The EMBO journal
JID - 8208664
RN  - 0 (Antigens, Differentiation, B-Lymphocyte)
RN  - 0 (Histocompatibility Antigens Class II)
RN  - 0 (Peptide Fragments)
RN  - 0 (Protease Inhibitors)
RN  - 0 (invariant chain)
RN  - 9010-34-8 (Thyroglobulin)
RN  - EC 3.4.- (Cathepsins)
RN  - EC 3.4.- (Endopeptidases)
RN  - EC 3.4.22.- (Cysteine Endopeptidases)
RN  - EC 3.4.22.15 (CTSL protein, human)
RN  - EC 3.4.22.15 (Cathepsin L)
RN  - EC 3.4.22.27 (cathepsin S)
SB  - IM
MH  - Amino Acid Sequence
MH  - Antigens, Differentiation, B-Lymphocyte/*chemistry
MH  - Binding Sites
MH  - Cathepsin L
MH  - Cathepsins/*chemistry
MH  - Crystallography, X-Ray
MH  - Cysteine Endopeptidases
MH  - *Endopeptidases
MH  - Histocompatibility Antigens Class II/*chemistry
MH  - Humans
MH  - Kidney/enzymology
MH  - Molecular Sequence Data
MH  - Peptide Fragments/chemistry
MH  - Protease Inhibitors/chemistry
MH  - Protein Conformation
MH  - Protein Folding
MH  - Protein Structure, Secondary
MH  - Sequence Alignment
MH  - Substrate Specificity
MH  - Thyroglobulin/chemistry
PMC - PMC1171172
EDAT- 1999/02/18 00:00
MHDA- 1999/02/18 00:01
CRDT- 1999/02/18 00:00
PHST- 1999/02/18 00:00 [pubmed]
PHST- 1999/02/18 00:01 [medline]
PHST- 1999/02/18 00:00 [entrez]
AID - 10.1093/emboj/18.4.793 [doi]
PST - ppublish
SO  - EMBO J. 1999 Feb 15;18(4):793-803. doi: 10.1093/emboj/18.4.793.