PDBsum entry 3b4r

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Hydrolase PDB id
Protein chains
218 a.a. *
_ZN ×2
* Residue conservation analysis
PDB id:
Name: Hydrolase
Title: Site-2 protease from methanocaldococcus jannaschii
Structure: Putative zinc metalloprotease mj0392. Chain: a, b. Fragment: site-2 protease residues 1-224. Engineered: yes
Source: Methanocaldococcus jannaschii. Organism_taxid: 2190. Expressed in: escherichia coli. Expression_system_taxid: 562.
3.30Å     R-factor:   0.251     R-free:   0.318
Authors: P.D.Jeffrey,L.Feng,H.Yan,Z.Wu,N.Yan,Z.Wang,Y.Shi
Key ref:
L.Feng et al. (2007). Structure of a site-2 protease family intramembrane metalloprotease. Science, 318, 1608-1612. PubMed id: 18063795 DOI: 10.1126/science.1150755
24-Oct-07     Release date:   15-Jan-08    
Go to PROCHECK summary

Protein chains
Pfam   ArchSchema ?
Q57837  (Y392_METJA) -  Zinc metalloprotease MJ0392
339 a.a.
218 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Gene Ontology (GO) functional annotation 
  GO annot!
  Biological process     proteolysis   1 term 
  Biochemical function     metalloendopeptidase activity     1 term  


DOI no: 10.1126/science.1150755 Science 318:1608-1612 (2007)
PubMed id: 18063795  
Structure of a site-2 protease family intramembrane metalloprotease.
L.Feng, H.Yan, Z.Wu, N.Yan, Z.Wang, P.D.Jeffrey, Y.Shi.
Regulated intramembrane proteolysis by members of the site-2 protease (S2P) family is an important signaling mechanism conserved from bacteria to humans. Here we report the crystal structure of the transmembrane core domain of an S2P metalloprotease from Methanocaldococcus jannaschii. The protease consists of six transmembrane segments, with the catalytic zinc atom coordinated by two histidine residues and one aspartate residue approximately 14 angstroms into the lipid membrane surface. The protease exhibits two distinct conformations in the crystals. In the closed conformation, the active site is surrounded by transmembrane helices and is impermeable to substrate peptide; water molecules gain access to zinc through a polar, central channel that opens to the cytosolic side. In the open conformation, transmembrane helices alpha1 and alpha6 separate from each other by 10 to 12 angstroms, exposing the active site to substrate entry. The structure reveals how zinc embedded in an integral membrane protein can catalyze peptide cleavage.
  Selected figure(s)  
Figure 3.
Fig. 3. Access of water molecules to the active site of mjS2P. (A) The van der Waals surface in molecule B reveals a channel that leads to the active site from the cytosolic side. The calculation was performed with the program HOLE (31) and the image was generated using VMD (32). The center line of the channel is colored magenta. (B) The channel is large enough to allow passage of water molecules. Distance from the zinc atom along the center line of the channel is plotted against the minimal radius at each point. The red line indicates the minimal radius required for passage of water molecules. (C) The channel is lined with polar groups that may help facilitate water entry. Shown here is a view of the polar groups in the channel approximately along the center line. Five carbonyl oxygen atoms, Arg^151, and Glu^207 are positioned along the inside of the channel.
Figure 4.
Fig. 4. Mechanism of substrate gating in mjS2P. (A) Surface representation of the closed state of mjS2P in two perpendicular views. Note the closure of the active site. (B) Surface representation of the open state of mjS2P in two perpendicular views. In this conformation, an extended polypeptide can be readily fitted into the cleft between the two gating helices ( 1 and 6). (A) and (B) were prepared using GRASP (33). (C) A proposed general model for the S2P family of intramembrane proteases. In this model, substrate entry to the active site is gated by two transmembrane segments, TM1 and TM6-TM5.
  The above figures are reprinted by permission from the AAAs: Science (2007, 318, 1608-1612) copyright 2007.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
23254937 M.S.Wolfe (2013).
Structural biology: Membrane enzyme cuts a fine figure.
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23254940 X.Li, S.Dang, C.Yan, X.Gong, J.Wang, and Y.Shi (2013).
Structure of a presenilin family intramembrane aspartate protease.
  Nature, 493, 56-61.
PDB codes: 4hyc 4hyd 4hyg
20938980 K.Illergård, A.Kauko, and A.Elofsson (2011).
Why are polar residues within the membrane core evolutionary conserved?
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  20927381 C.Torres-Arancivia, C.M.Ross, J.Chavez, Z.Assur, G.Dolios, F.Mancia, and I.Ubarretxena-Belandia (2010).
Identification of an archaeal presenilin-like intramembrane protease.
  PLoS One, 5, 0.  
20836086 G.Chen, and X.Zhang (2010).
New insights into S2P signaling cascades: regulation, variation, and conservation.
  Protein Sci, 19, 2015-2030.  
20207753 J.X.Liu, and S.H.Howell (2010).
bZIP28 and NF-Y transcription factors are activated by ER stress and assemble into a transcriptional complex to regulate stress response genes in Arabidopsis.
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19826804 K.McLuskey, A.W.Roszak, Y.Zhu, and N.W.Isaacs (2010).
Crystal structures of all-alpha type membrane proteins.
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20667175 K.R.Vinothkumar, and R.Henderson (2010).
Structures of membrane proteins.
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20482315 M.S.Wolfe (2010).
Structure, mechanism and inhibition of gamma-secretase and presenilin-like proteases.
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20445084 S.Sobhanifar, B.Schneider, F.Löhr, D.Gottstein, T.Ikeya, K.Mlynarczyk, W.Pulawski, U.Ghoshdastider, M.Kolinski, S.Filipek, P.Güntert, F.Bernhard, and V.Dötsch (2010).
Structural investigation of the C-terminal catalytic fragment of presenilin 1.
  Proc Natl Acad Sci U S A, 107, 9644-9649.  
20070259 S.Urban (2010).
Taking the plunge: integrating structural, enzymatic and computational insights into a unified model for membrane-immersed rhomboid proteolysis.
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19778442 A.J.Bordner (2009).
Predicting protein-protein binding sites in membrane proteins.
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19007897 A.Tolia, and B.De Strooper (2009).
Structure and function of gamma-secretase.
  Semin Cell Dev Biol, 20, 211-218.  
19818023 C.M.Bien, Y.C.Chang, W.D.Nes, K.J.Kwon-Chung, and P.J.Espenshade (2009).
Cryptococcus neoformans Site-2 protease is required for virulence and survival in the presence of azole drugs.
  Mol Microbiol, 74, 672-690.  
19729449 D.R.Dries, S.Shah, Y.H.Han, C.Yu, S.Yu, M.S.Shearman, and G.Yu (2009).
Glu-333 of nicastrin directly participates in gamma-secretase activity.
  J Biol Chem, 284, 29714-29724.  
19458713 E.Erez, D.Fass, and E.Bibi (2009).
How intramembrane proteases bury hydrolytic reactions in the membrane.
  Nature, 459, 371-378.  
19278647 H.Li, M.S.Wolfe, and D.J.Selkoe (2009).
Toward structural elucidation of the gamma-secretase complex.
  Structure, 17, 326-334.  
18849157 J.Dai, Z.Li, J.Jin, Y.Shi, J.Cheng, J.Kong, and S.Bi (2009).
Some thoughts on the existence of ion and water channels in highly dense and well-ordered CH3-terminated alkanethiol self-assembled monolayers on gold.
  Biosens Bioelectron, 24, 1074-1082.  
19346249 J.Hu, M.Sharma, H.Qin, F.P.Gao, and T.A.Cross (2009).
Ligand binding in the conserved interhelical loop of CorA, a magnesium transporter from Mycobacterium tuberculosis.
  J Biol Chem, 284, 15619-15628.  
19015545 K.A.Matthews, A.S.Kunte, E.Tambe-Ebot, and R.B.Rawson (2009).
Alternative Processing of Sterol Regulatory Element Binding Protein During Larval Development in Drosophila melanogaster.
  Genetics, 181, 119-128.  
18974038 M.S.Brown, and J.L.Goldstein (2009).
Cholesterol feedback: from Schoenheimer's bottle to Scap's MELADL.
  J Lipid Res, 50, S15-S27.  
19189971 M.S.Wolfe (2009).
Intramembrane-cleaving proteases.
  J Biol Chem, 284, 13969-13973.  
19226105 M.S.Wolfe (2009).
Intramembrane proteolysis.
  Chem Rev, 109, 1599-1612.  
19171975 P.D.Jeffrey (2009).
Analysis of errors in the structure determination of MsbA.
  Acta Crystallogr D Biol Crystallogr, 65, 193-199.  
19013469 P.Osenkowski, H.Li, W.Ye, D.Li, L.Aeschbach, P.C.Fraering, M.S.Wolfe, D.J.Selkoe, and H.Li (2009).
Cryoelectron microscopy structure of purified gamma-secretase at 12 A resolution.
  J Mol Biol, 385, 642-652.  
19805276 R.Zhou, C.Cusumano, D.Sui, R.M.Garavito, and L.Kroos (2009).
Intramembrane proteolytic cleavage of a membrane-tethered transcription factor by a metalloprotease depends on ATP.
  Proc Natl Acad Sci U S A, 106, 16174-16179.  
19458709 S.H.White (2009).
Biophysical dissection of membrane proteins.
  Nature, 459, 344-346.  
19421188 S.Urban (2009).
Making the cut: central roles of intramembrane proteolysis in pathogenic microorganisms.
  Nat Rev Microbiol, 7, 411-423.  
19164538 T.Sato, T.C.Tang, G.Reubins, J.Z.Fei, T.Fujimoto, P.Kienlen-Campard, S.N.Constantinescu, J.N.Octave, S.Aimoto, and S.O.Smith (2009).
A helix-to-coil transition at the epsilon-cut site in the transmembrane dimer of the amyloid precursor protein is required for proteolysis.
  Proc Natl Acad Sci U S A, 106, 1421-1426.  
19059492 Y.Ha (2009).
Structure and mechanism of intramembrane protease.
  Semin Cell Dev Biol, 20, 240-250.  
18230615 C.Coffinier, S.E.Hudon, R.Lee, E.A.Farber, C.Nobumori, J.H.Miner, D.A.Andres, H.P.Spielmann, C.A.Hrycyna, L.G.Fong, and S.G.Young (2008).
A potent HIV protease inhibitor, darunavir, does not inhibit ZMPSTE24 or lead to an accumulation of farnesyl-prelamin A in cells.
  J Biol Chem, 283, 9797-9804.  
18559471 R.B.Rawson (2008).
Intriguing parasites and intramembrane proteases.
  Genes Dev, 22, 1561-1566.  
18983936 S.E.Ades (2008).
Regulation by destruction: design of the sigmaE envelope stress response.
  Curr Opin Microbiol, 11, 535-540.  
18979634 S.Urban, and R.P.Baker (2008).
In vivo analysis reveals substrate-gating mutants of a rhomboid intramembrane protease display increased activity in living cells.
  Biol Chem, 389, 1107-1115.  
18440799 S.Urban, and Y.Shi (2008).
Core principles of intramembrane proteolysis: comparison of rhomboid and site-2 family proteases.
  Curr Opin Struct Biol, 18, 432-441.  
18158892 M.K.Lemberg, and M.Freeman (2007).
Cutting proteins within lipid bilayers: rhomboid structure and mechanism.
  Mol Cell, 28, 930-940.  
The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time. Where a reference describes a PDB structure, the PDB codes are shown on the right.