PDBsum entry 1auk

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Hydrolase PDB id
Protein chain
481 a.a. *
Waters ×176
* Residue conservation analysis
PDB id:
Name: Hydrolase
Title: Human arylsulfatase a
Structure: Arylsulfatase a. Chain: a. Synonym: cerebroside-3-sulfate-sulfatase. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Organ: testis. Cellular_location: lysosome. Gene: arsa. Expressed in: mesocricetus auratus. Expression_system_taxid: 10036. Expression_system_cell_line: baby hamster kidney cells (bhk
Biol. unit: Dimer (from PQS)
2.10Å     R-factor:   0.248     R-free:   0.273
Authors: G.Lukatela,N.Krauss,K.Theis,V.Gieselmann,K.Von Figura,W.Saen
Key ref:
G.Lukatela et al. (1998). Crystal structure of human arylsulfatase A: the aldehyde function and the metal ion at the active site suggest a novel mechanism for sulfate ester hydrolysis. Biochemistry, 37, 3654-3664. PubMed id: 9521684 DOI: 10.1021/bi9714924
29-Aug-97     Release date:   04-Mar-98    
Go to PROCHECK summary

Protein chain
Pfam   ArchSchema ?
P15289  (ARSA_HUMAN) -  Arylsulfatase A
507 a.a.
481 a.a.*
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 1 residue position (black cross)

 Enzyme reactions 
   Enzyme class: E.C.  - Cerebroside-sulfatase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: A cerebroside 3-sulfate + H2O = a cerebroside + sulfate
cerebroside 3-sulfate
+ H(2)O
= cerebroside
+ sulfate
Molecule diagrams generated from .mol files obtained from the KEGG ftp site
 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     extracellular space   11 terms 
  Biological process     metabolic process   14 terms 
  Biochemical function     catalytic activity     7 terms  


DOI no: 10.1021/bi9714924 Biochemistry 37:3654-3664 (1998)
PubMed id: 9521684  
Crystal structure of human arylsulfatase A: the aldehyde function and the metal ion at the active site suggest a novel mechanism for sulfate ester hydrolysis.
G.Lukatela, N.Krauss, K.Theis, T.Selmer, V.Gieselmann, K.von Figura, W.Saenger.
Human lysosomal arylsulfatase A (ASA) is a prototype member of the sulfatase family. These enzymes require the posttranslational oxidation of the -CH2SH group of a conserved cysteine to an aldehyde, yielding a formylglycine. Without this modification sulfatases are catalytically inactive, as revealed by a lysosomal storage disorder known as multiple sulfatase deficiency. The 2.1 A resolution X-ray crystal structure shows an ASA homooctamer composed of a tetramer of dimers, (alpha 2)4. The alpha/beta fold of the monomer has significant structural analogy to another hydrolytic enzyme, the alkaline phosphatase, and superposition of these two structures shows that the active centers are located in largely identical positions. The functionally essential formylglycine is located in a positively charged pocket and acts as ligand to an octahedrally coordinated metal ion interpreted as Mg2+. The electron density at the formylglycine suggests the presence of a 2-fold disordered aldehyde group with the possible contribution of an aldehyde hydrate, -CH(OH)2, with gem-hydroxyl groups. In the proposed catalytic mechanism, the aldehyde accepts a water molecule to form a hydrate. One of the two hydroxyl groups hydrolyzes the substrate sulfate ester via a transesterification step, resulting in a covalent intermediate. The second hydroxyl serves to eliminate sulfate under inversion of configuration through C-O cleavage and reformation of the aldehyde. This study provides the structural basis for understanding a novel mechanism of ester hydrolysis and explains the functional importance of the unusually modified amino acid.

Literature references that cite this PDB file's key reference

  PubMed id Reference
19826804 K.McLuskey, A.W.Roszak, Y.Zhu, and N.W.Isaacs (2010).
Crystal structures of all-alpha type membrane proteins.
  Eur Biophys J, 39, 723-755.  
20165970 M.Buono, and M.P.Cosma (2010).
Sulfatase activities towards the regulation of cell metabolism and signaling in mammals.
  Cell Mol Life Sci, 67, 769-780.  
20442248 R.Gill, L.Hitchins, F.Fletcher, and G.K.Dhoot (2010).
Sulf1A and HGF regulate satellite-cell growth.
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19726671 J.R.Myette, V.Soundararajan, Z.Shriver, R.Raman, and R.Sasisekharan (2009).
Heparin/heparan sulfate 6-O-sulfatase from Flavobacterium heparinum: integrated structural and biochemical investigation of enzyme active site and substrate specificity.
  J Biol Chem, 284, 35177-35188.  
19734177 M.M.Hossain, Y.Kawarabayasi, M.Kimura, and Y.Kakuta (2009).
Expression and functional analysis of a predicted AtsG arylsulphatase identified from Mycobacterium tuberculosis genomic data.
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19381802 M.Schenk, C.A.Koppisetty, D.C.Santos, E.Carmona, S.Bhatia, P.G.Nyholm, and N.Tanphaichitr (2009).
Interaction of arylsulfatase-A (ASA) with its natural sulfoglycolipid substrates: a computational and site-directed mutagenesis study.
  Glycoconj J, 26, 1029-1045.  
19675886 M.Sunbul, and J.Yin (2009).
Site specific protein labeling by enzymatic posttranslational modification.
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19520866 R.Tang, and S.D.Rosen (2009).
Functional consequences of the subdomain organization of the sulfs.
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19790257 T.S.Kang, and R.C.Stevens (2009).
Structural aspects of therapeutic enzymes to treat metabolic disorders.
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18501204 A.L.Parrill (2008).
Lysophospholipid interactions with protein targets.
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18390551 B.L.Carlson, E.R.Ballister, E.Skordalakes, D.S.King, M.A.Breidenbach, S.A.Gilmore, J.M.Berger, and C.R.Bertozzi (2008).
Function and structure of a prokaryotic formylglycine-generating enzyme.
  J Biol Chem, 283, 20117-20125.
PDB code: 2q17
17847089 K.Goyal, and S.C.Mande (2008).
Exploiting 3D structural templates for detection of metal-binding sites in protein structures.
  Proteins, 70, 1206-1218.  
18178549 M.Mariappan, K.Radhakrishnan, T.Dierks, B.Schmidt, and K.von Figura (2008).
ERp44 mediates a thiol-independent retention of formylglycine-generating enzyme in the endoplasmic reticulum.
  J Biol Chem, 283, 6375-6383.  
18288656 P.Bojarová, E.Denehy, I.Walker, K.Loft, D.P.De Souza, L.W.Woo, B.V.Potter, M.J.McConville, and S.J.Williams (2008).
Direct evidence for ArO-S bond cleavage upon inactivation of Pseudomonas aeruginosa arylsulfatase by aryl sulfamates.
  Chembiochem, 9, 613-623.  
18625336 P.Bojarová, and S.J.Williams (2008).
Sulfotransferases, sulfatases and formylglycine-generating enzymes: a sulfation fascination.
  Curr Opin Chem Biol, 12, 573-581.  
18266766 S.L.Gande, M.Mariappan, B.Schmidt, T.H.Pringle, K.von Figura, and T.Dierks (2008).
Paralog of the formylglycine-generating enzyme--retention in the endoplasmic reticulum by canonical and noncanonical signals.
  FEBS J, 275, 1118-1130.  
18558715 T.L.Grove, K.H.Lee, J.St Clair, C.Krebs, and S.J.Booker (2008).
In vitro characterization of AtsB, a radical SAM formylglycine-generating enzyme that contains three [4Fe-4S] clusters.
  Biochemistry, 47, 7523-7538.  
17876718 A.M.Montaño, K.Sukegawa, Z.Kato, R.Carrozzo, P.Di Natale, E.Christensen, K.O.Orii, T.Orii, N.Kondo, and S.Tomatsu (2007).
Effect of 'attenuated' mutations in mucopolysaccharidosis IVA on molecular phenotypes of N-acetylgalactosamine-6-sulfate sulfatase.
  J Inherit Metab Dis, 30, 758-767.  
17474085 A.Wu, A.Anupriwan, S.Iamsaard, K.Chakrabandhu, D.C.Santos, T.Rupar, B.K.Tsang, E.Carmona, and N.Tanphaichitr (2007).
Sperm surface arylsulfatase A can disperse the cumulus matrix of cumulus oocyte complexes.
  J Cell Physiol, 213, 201-211.  
17413447 H.G.Kumperscak, B.K.Plesnicar, B.Zalar, P.Gradisnik, T.Seruga, and E.Paschke (2007).
Adult metachromatic leukodystrophy: a new mutation in the schizophrenia-like phenotype with early neurological signs.
  Psychiatr Genet, 17, 85-91.  
17085493 M.Nukui, L.V.Mello, J.E.Littlejohn, B.Setlow, P.Setlow, K.Kim, T.Leighton, and M.J.Jedrzejas (2007).
Structure and molecular mechanism of Bacillus anthracis cofactor-independent phosphoglycerate mutase: a crucial enzyme for spores and growing cells of Bacillus species.
  Biophys J, 92, 977-988.
PDB code: 2ify
17091340 K.Sukegawa-Hayasaka, Z.Kato, H.Nakamura, S.Tomatsu, T.Fukao, K.Kuwata, T.Orii, and N.Kondo (2006).
Effect of Hunter disease (mucopolysaccharidosis type II) mutations on molecular phenotypes of iduronate-2-sulfatase: enzymatic activity, protein processing and structural analysis.
  J Inherit Metab Dis, 29, 755-761.  
16766528 O.Berteau, A.Guillot, A.Benjdia, and S.Rabot (2006).
A new type of bacterial sulfatase reveals a novel maturation pathway in prokaryotes.
  J Biol Chem, 281, 22464-22470.  
16899453 R.L.Felts, T.J.Reilly, and J.J.Tanner (2006).
Structure of Francisella tularensis AcpA: prototype of a unique superfamily of acid phosphatases and phospholipases C.
  J Biol Chem, 281, 30289-30298.
PDB code: 2d1g
17045481 S.R.Hanson, L.J.Whalen, and C.H.Wong (2006).
Synthesis and evaluation of general mechanism-based inhibitors of sulfatases based on (difluoro)methyl phenyl sulfate and cyclic phenyl sulfamate motifs.
  Bioorg Med Chem, 14, 8386-8395.  
15657036 A.Preusser-Kunze, M.Mariappan, B.Schmidt, S.L.Gande, K.Mutenda, D.Wenzel, K.von Figura, and T.Dierks (2005).
Molecular characterization of the human Calpha-formylglycine-generating enzyme.
  J Biol Chem, 280, 14900-14910.  
16124866 G.Diez-Roux, and A.Ballabio (2005).
Sulfatases and human disease.
  Annu Rev Genomics Hum Genet, 6, 355-379.  
15906398 L.Poppe, and J.Rétey (2005).
Friedel-Crafts-type mechanism for the enzymatic elimination of ammonia from histidine and phenylalanine.
  Angew Chem Int Ed Engl, 44, 3668-3688.  
15708861 M.Mariappan, A.Preusser-Kunze, M.Balleininger, N.Eiselt, B.Schmidt, S.L.Gande, D.Wenzel, T.Dierks, and K.von Figura (2005).
Expression, localization, structural, and functional characterization of pFGE, the paralog of the Calpha-formylglycine-generating enzyme.
  J Biol Chem, 280, 15173-15179.  
15999201 S.R.Wallner, B.M.Nestl, and K.Faber (2005).
Highly enantioselective stereo-inverting sec-alkylsulfatase activity of hyperthermophilic Archaea.
  Org Biomol Chem, 3, 2652-2656.  
16161167 S.R.Wallner, M.Bauer, C.Würdemann, P.Wecker, F.O.Glöckner, and K.Faber (2005).
Highly enantioselective sec-alkyl sulfatase activity of the marine planctomycete Rhodopirellula baltica shows retention of configuration.
  Angew Chem Int Ed Engl, 44, 6381-6384.  
15326627 L.Berná, V.Gieselmann, H.Poupetová, M.Hrebícek, M.Elleder, and J.Ledvinová (2004).
Novel mutations associated with metachromatic leukodystrophy: phenotype and expression studies in nine Czech and Slovak patients.
  Am J Med Genet A, 129, 277-281.  
14749327 Q.Fang, J.Peng, and T.Dierks (2004).
Post-translational formylglycine modification of bacterial sulfatases by the radical S-adenosylmethionine protein AtsB.
  J Biol Chem, 279, 14570-14578.  
15048814 S.Hovmöller, and T.Zhou (2004).
Why are both ends of the polypeptide chain on the outside of proteins?
  Proteins, 55, 219-222.  
15493058 S.R.Hanson, M.D.Best, and C.H.Wong (2004).
Sulfatases: structure, mechanism, biological activity, inhibition, and synthetic utility.
  Angew Chem Int Ed Engl, 43, 5736-5763.  
12783870 A.Yaghootfam, F.Schestag, T.Dierks, and V.Gieselmann (2003).
Recognition of arylsulfatase A and B by the UDP-N-acetylglucosamine:lysosomal enzyme N-acetylglucosamine-phosphotransferase.
  J Biol Chem, 278, 32653-32661.  
12419807 C.Marquordt, Q.Fang, E.Will, J.Peng, K.von Figura, and T.Dierks (2003).
Posttranslational modification of serine to formylglycine in bacterial sulfatases. Recognition of the modification motif by the iron-sulfur protein AtsB.
  J Biol Chem, 278, 2212-2218.  
12657638 F.G.Hernandez-Guzman, T.Higashiyama, W.Pangborn, Y.Osawa, and D.Ghosh (2003).
Structure of human estrone sulfatase suggests functional roles of membrane association.
  J Biol Chem, 278, 22989-22997.
PDB code: 1p49
12777796 H.Xu, N.Sträter, W.Schröder, C.Böttcher, K.Ludwig, and W.Saenger (2003).
Structure of DNA helicase RepA in complex with sulfate at 1.95 A resolution implicates structural changes to an "open" form.
  Acta Crystallogr D Biol Crystallogr, 59, 815-822.
PDB code: 1nlf
12526009 J.Peng, B.Schmidt, K.von Figura, and T.Dierks (2003).
Identification of formylglycine in sulfatases by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry.
  J Mass Spectrom, 38, 80-86.  
12519775 J.R.Myette, Z.Shriver, C.Claycamp, M.W.McLean, G.Venkataraman, and R.Sasisekharan (2003).
The heparin/heparan sulfate 2-O-sulfatase from Flavobacterium heparinum. Molecular cloning, recombinant expression, and biochemical characterization.
  J Biol Chem, 278, 12157-12166.  
12757706 M.P.Cosma, S.Pepe, I.Annunziata, R.F.Newbold, M.Grompe, G.Parenti, and A.Ballabio (2003).
The multiple sulfatase deficiency gene encodes an essential and limiting factor for the activity of sulfatases.
  Cell, 113, 445-456.  
12519774 R.Raman, J.R.Myette, Z.Shriver, K.Pojasek, G.Venkataraman, and R.Sasisekharan (2003).
The heparin/heparan sulfate 2-O-sulfatase from Flavobacterium heparinum. A structural and biochemical study of the enzyme active site and saccharide substrate specificity.
  J Biol Chem, 278, 12167-12174.  
12757705 T.Dierks, B.Schmidt, L.V.Borissenko, J.Peng, A.Preusser, M.Mariappan, and K.von Figura (2003).
Multiple sulfatase deficiency is caused by mutations in the gene encoding the human C(alpha)-formylglycine generating enzyme.
  Cell, 113, 435-444.  
12081727 A.Lugowska, J.Berger, A.Tylki-Szymañska, B.Czartoryska, B.Löschl, and B.Molzer (2002).
High prevalence of I179S mutation in patients with late-onset metachromatic leukodystrophy.
  Clin Genet, 61, 389-390.  
12124990 B.N.Terp, D.N.Cooper, I.T.Christensen, F.S.Jørgensen, P.Bross, N.Gregersen, and M.Krawczak (2002).
Assessing the relative importance of the biophysical properties of amino acid substitutions associated with human genetic disease.
  Hum Mutat, 20, 98.  
12144918 J.D.Mougous, R.E.Green, S.J.Williams, S.E.Brenner, and C.R.Bertozzi (2002).
Sulfotransferases and sulfatases in mycobacteria.
  Chem Biol, 9, 767-776.  
12496078 P.Vagedes, W.Saenger, and E.W.Knapp (2002).
Driving forces of protein association: the dimer-octamer equilibrium in arylsulfatase A.
  Biophys J, 83, 3066-3078.  
11777924 R.von Bülow, B.Schmidt, T.Dierks, N.Schwabauer, K.Schilling, E.Weber, I.Usón, and K.von Figura (2002).
Defective oligomerization of arylsulfatase a as a cause of its instability in lysosomes and metachromatic leukodystrophy.
  J Biol Chem, 277, 9455-9461.
PDB code: 1e33
11895481 T.Ohto, H.Uchida, H.Yamazaki, K.Keino-Masu, A.Matsui, and M.Masu (2002).
Identification of a novel nonlysosomal sulphatase expressed in the floor plate, choroid plexus and cartilage.
  Genes Cells, 7, 173-185.  
12115126 V.V.Mozhaev, Y.L.Khmelnitsky, F.Sanchez-Riera, J.Maurina-Brunker, R.A.Rosson, and A.D.Grund (2002).
Arylsulfotransferase from Clostridium innocuum-A new enzyme catalyst for sulfation of phenol-containing compounds.
  Biotechnol Bioeng, 78, 567-575.  
11533491 G.K.Dhoot, M.K.Gustafsson, X.Ai, W.Sun, D.M.Standiford, and C.P.Emerson (2001).
Regulation of Wnt signaling and embryo patterning by an extracellular sulfatase.
  Science, 293, 1663-1666.  
11668611 G.Yogalingam, and J.J.Hopwood (2001).
Molecular genetics of mucopolysaccharidosis type IIIA and IIIB: Diagnostic, clinical, and biological implications.
  Hum Mutat, 18, 264-281.  
11435113 I.Boltes, H.Czapinska, A.Kahnert, R.von Bülow, T.Dierks, B.Schmidt, K.von Figura, M.A.Kertesz, and I.Usón (2001).
1.3 A structure of arylsulfatase from Pseudomonas aeruginosa establishes the catalytic mechanism of sulfate ester cleavage in the sulfatase family.
  Structure, 9, 483-491.
PDB code: 1hdh
11600503 J.Fey, M.Balleininger, L.V.Borissenko, B.Schmidt, K.von Figura, and T.Dierks (2001).
Characterization of posttranslational formylglycine formation by luminal components of the endoplasmic reticulum.
  J Biol Chem, 276, 47021-47028.  
11746679 M.Y.Galperin, and M.J.Jedrzejas (2001).
Conserved core structure and active site residues in alkaline phosphatase superfamily enzymes.
  Proteins, 45, 318-324.  
10809675 D.P.Wright, C.G.Knight, S.G.Parkar, D.L.Christie, and A.M.Roberton (2000).
Cloning of a mucin-desulfating sulfatase gene from Prevotella strain RS2 and its expression using a Bacteroides recombinant system.
  J Bacteriol, 182, 3002-3007.  
10948126 J.A.Hoffman, J.L.Badger, Y.Zhang, S.H.Huang, and K.S.Kim (2000).
Escherichia coli K1 aslA contributes to invasion of brain microvascular endothelial cells in vitro and in vivo.
  Infect Immun, 68, 5062-5067.  
10771439 K.Lewinski, M.Chruszcz, D.Ksiazek, and P.Laidler (2000).
Crystallization and preliminary crystallographic analysis of a new crystal form of arylsulfatase A isolated from human placenta.
  Acta Crystallogr D Biol Crystallogr, 56, 650-652.  
11033081 L.L.Woo, A.Purohit, B.Malini, M.J.Reed, and B.V.Potter (2000).
Potent active site-directed inhibition of steroid sulphatase by tricyclic coumarin-based sulphamates.
  Chem Biol, 7, 773-791.  
10717312 M.A.Kertesz (2000).
Riding the sulfur cycle--metabolism of sulfonates and sulfate esters in gram-negative bacteria.
  FEMS Microbiol Rev, 24, 135-175.  
10903941 N.M.Okeley, and W.A.van der Donk (2000).
Novel cofactors via post-translational modifications of enzyme active sites.
  Chem Biol, 7, R159-R171.  
10727844 S.Esposito, N.Balzano, A.Daniele, G.R.Villani, K.Perkins, B.Weber, J.J.Hopwood, and P.Di Natale (2000).
Heparan N-sulfatase gene: two novel mutations and transient expression of 15 defects.
  Biochim Biophys Acta, 1501, 1.  
10751093 S.Hermann, F.Schestag, A.Polten, S.Kafert, J.Penzien, J.Zlotogora, N.Baumann, and V.Gieselmann (2000).
Characterization of four arylsulfatase A missense mutations G86D, Y201C, D255H, and E312D causing metachromatic leukodystrophy.
  Am J Med Genet, 91, 68-73.  
9920914 A.Schierau, F.Dietz, H.Lange, F.Schestag, A.Parastar, and V.Gieselmann (1999).
Interaction of arylsulfatase A with UDP-N-acetylglucosamine:Lysosomal enzyme-N-acetylglucosamine-1-phosphotransferase.
  J Biol Chem, 274, 3651-3658.  
10212197 A.Waldow, B.Schmidt, T.Dierks, R.von Bülow, and K.von Figura (1999).
Amino acid residues forming the active site of arylsulfatase A. Role in catalytic activity and substrate binding.
  J Biol Chem, 274, 12284-12288.  
10336424 C.Szameit, C.Miech, M.Balleininger, B.Schmidt, K.von Figura, and T.Dierks (1999).
The iron sulfur protein AtsB is required for posttranslational formation of formylglycine in the Klebsiella sulfatase.
  J Biol Chem, 274, 15375-15381.  
10601282 K.J.Perkins, S.Byers, G.Yogalingam, B.Weber, and J.J.Hopwood (1999).
Expression and characterization of wild type and mutant recombinant human sulfamidase. Implications for Sanfilippo (Mucopolysaccharidosis IIIA) syndrome.
  J Biol Chem, 274, 37193-37199.  
10099128 P.J.O'Brien, and D.Herschlag (1999).
Catalytic promiscuity and the evolution of new enzymatic activities.
  Chem Biol, 6, R91.  
10591107 S.S.Brody, S.P.Gough, and C.G.Kannangara (1999).
Predicted structure and fold recognition for the glutamyl tRNA reductase family of proteins.
  Proteins, 37, 485-493.
PDB codes: 1b29 1b61
10205163 T.Dierks, M.R.Lecca, P.Schlotterhose, B.Schmidt, and K.von Figura (1999).
Sequence determinants directing conversion of cysteine to formylglycine in eukaryotic sulfatases.
  EMBO J, 18, 2084-2091.  
9760228 A.Knaust, B.Schmidt, T.Dierks, R.von Bülow, and K.von Figura (1998).
Residues critical for formylglycine formation and/or catalytic activity of arylsulfatase A.
  Biochemistry, 37, 13941-13946.  
  10082381 M.Y.Galperin, A.Bairoch, and E.V.Koonin (1998).
A superfamily of metalloenzymes unifies phosphopentomutase and cofactor-independent phosphoglycerate mutase with alkaline phosphatases and sulfatases.
  Protein Sci, 7, 1829-1835.  
9810225 S.Melino, C.Capo, B.Dragani, A.Aceto, and R.Petruzzelli (1998).
A zinc-binding motif conserved in glyoxalase II, beta-lactamase and arylsulfatases.
  Trends Biochem Sci, 23, 381-382.  
9748219 T.Dierks, C.Miech, J.Hummerjohann, B.Schmidt, M.A.Kertesz, and K.von Figura (1998).
Posttranslational formation of formylglycine in prokaryotic sulfatases by modification of either cysteine or serine.
  J Biol Chem, 273, 25560-25564.  
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 code is shown on the right.