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PDBsum entry 1amh

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Hydrolase PDB id
1amh
Jmol
Contents
Protein chains
223 a.a. *
Metals
_CA ×2
Waters ×128
* Residue conservation analysis
PDB id:
1amh
Name: Hydrolase
Title: Uncomplexed rat trypsin mutant with asp 189 replaced with ser (d189s)
Structure: Anionic trypsin. Chain: a, b. Engineered: yes. Mutation: yes
Source: Rattus rattus. Black rat. Organism_taxid: 10117. Organ: pancreas. Expressed in: saccharomyces cerevisiae. Expression_system_taxid: 4932.
Biol. unit: Dimer (from PQS)
Resolution:
2.50Å     R-factor:   0.182     R-free:   0.242
Authors: E.Szabo,Z.S.Bocskei,G.Naray-Szabo,L.Graf
Key ref:
J.J.Perona and C.S.Craik (1995). Structural basis of substrate specificity in the serine proteases. Protein Sci, 4, 337-360. PubMed id: 7795518 DOI: 10.1002/pro.5560040301
Date:
17-Jun-97     Release date:   24-Dec-97    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chains
Pfam   ArchSchema ?
P00763  (TRY2_RAT) -  Anionic trypsin-2
Seq:
Struc:
246 a.a.
223 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.3.4.21.4  - Trypsin.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: Preferential cleavage: Arg-|-Xaa, Lys-|-Xaa.
 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     cellular_component   3 terms 
  Biological process     digestion   4 terms 
  Biochemical function     catalytic activity     8 terms  

 

 
DOI no: 10.1002/pro.5560040301 Protein Sci 4:337-360 (1995)
PubMed id: 7795518  
 
 
Structural basis of substrate specificity in the serine proteases.
J.J.Perona, C.S.Craik.
 
  ABSTRACT  
 
Structure-based mutational analysis of serine protease specificity has produced a large database of information useful in addressing biological function and in establishing a basis for targeted design efforts. Critical issues examined include the function of water molecules in providing strength and specificity of binding, the extent to which binding subsites are interdependent, and the roles of polypeptide chain flexibility and distal structural elements in contributing to specificity profiles. The studies also provide a foundation for exploring why specificity modification can be either straightforward or complex, depending on the particular system.
 
  Selected figure(s)  
 
Figure 2.
Fig. 2. Chemicalandkineticmechanisms of catalysis for serineprote- ases. Thecatalyticgroupsoftrypsin A) ndsubtilisin (B) areshown interactingwith an oligopptidesubstratebindingtothe PI-P4 sites. (Nomenclatureforthesubstrateaminoacid residues is Pn, . . . , P2, P1, PI', 2', . , Pn' where PI-PI' denotesthehydrolyzedbond. Sn, . . . , S2, SI, Sl', S2', . . . , Sn' denotethecorrespondingenzymebinding sites [Schechter & Berger, 19681.) Notethedistinctioinresiduesthatform theoxyanionhole;insubtilisin,part of theinteraction is mdebyan enzymesidechain.Thebindinsite for theoligopeptidealsodiffers; in subtilisin ormsthecentralstrandofathre-strandedatiparallel p- sheet.The SI site of trypsinandthe and 4 sites of ubtilisin aethe majorsiteswheremutagenesishasbeen used to probespecificity. : Common kineticmechanism f catalysis for serineproteasesindicating themeaning of themechanisticrateconstantsandtheirrelationshipto theMichaelisparameters.Thecorrectinterpretation kc=, and K,,, dif- fersdepending on therate-limitingstep in catalysis, which varies among thedifferentenzymesas well asamongdifferingsubstrates f thesame enzyme.
Figure 9.
Fig. 9. Principalrationale for theability of cy-lytic proteasemutants to exhibitgreatlyenhanced specificities towardnewsubstrtesidechains isstructuraplasticity of the S1 site. Shown is superposition of five structures of theM192Avariant of theenzye(the new Ala 192 side chain is at the right side). Eachenzymeiscomplexedwith a peptidyl bo- ronateinhibitor(otshown for clarity)possessingaparticuarhydro- phobicP1-sidchain (see Fig. 8 forinhibitorbinding).Theconformation of theactive site adjusts to thedifferentsubstratesat position Gly 16 andinte following oop region (bottom). othside-chainandmain- chainrearrangemensareimportant components f active-siteplastic- Theability of theactive site to adjust in thismannermaybean mportantfactorintheability to effect specificitymodification ymu- at only asingle site.
 
  The above figures are reprinted by permission from the Protein Society: Protein Sci (1995, 4, 337-360) copyright 1995.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

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18496527 T.Krojer, J.Sawa, E.Schäfer, H.R.Saibil, M.Ehrmann, and T.Clausen (2008).
Structural basis for the regulated protease and chaperone function of DegP.
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PDB codes: 2zle 3cs0
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Expansion of the mast cell chymase locus over the past 200 million years of mammalian evolution.
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Rapid lineage-specific diversification of the mast cell chymase locus during mammalian evolution.
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[Native and modified subtilisin Karlsberg as an effective catalyst of peptide bond formation in organic media]
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Functionalized magnetic micro- and nanoparticles: optimization and application to micro-chip tryptic digestion.
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Rapid analysis of Forster resonance energy transfer by two-color global fluorescence correlation spectroscopy: trypsin proteinase reaction.
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Stability of mutant serpin/furin complexes: dependence on pH and regulation at the deacylation step.
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16237016 E.Matsuda, N.Abe, H.Tamakawa, J.Kaneko, and Y.Kamio (2005).
Gene cloning and molecular characterization of an extracellular poly(L-lactic acid) depolymerase from Amycolatopsis sp. strain K104-1.
  J Bacteriol, 187, 7333-7340.  
16331328 H.M.Jiao, L.X.Yang, B.Lu, Y.Q.Wu, and Y.C.Zhou (2005).
Shedaoenase, a novel fibrinogenase from the venom of Agkistrodon shedaoenthesis Zhao.
  Acta Biochim Biophys Sin (Shanghai), 37, 835-842.  
15678420 M.Groll, M.Bochtler, H.Brandstetter, T.Clausen, and R.Huber (2005).
Molecular machines for protein degradation.
  Chembiochem, 6, 222-256.  
15634266 S.Krishnaswamy (2005).
Exosite-driven substrate specificity and function in coagulation.
  J Thromb Haemost, 3, 54-67.  
15923233 W.Ma, C.Tang, and L.Lai (2005).
Specificity of trypsin and chymotrypsin: loop-motion-controlled dynamic correlation as a determinant.
  Biophys J, 89, 1183-1193.  
15456490 A.Zivelin, T.Ogawa, S.Bulvik, M.Landau, J.R.Toomey, J.Lane, U.Seligsohn, and D.Gailani (2004).
Severe factor XI deficiency caused by a Gly555 to Glu mutation (factor XI-Glu555): a cross-reactive material positive variant defective in factor IX activation.
  J Thromb Haemost, 2, 1782-1789.  
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Crystal structure of the HGF beta-chain in complex with the Sema domain of the Met receptor.
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PDB code: 1shy
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The hsp70 chaperone DnaK is a secondary amide peptide bond cis-trans isomerase.
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Synergistic activation of ENaC by three membrane-bound channel-activating serine proteases (mCAP1, mCAP2, and mCAP3) and serum- and glucocorticoid-regulated kinase (Sgk1) in Xenopus Oocytes.
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Histidine 210 mutant of a trypsin-type Achromobacter protease I shows broad optimum pH range.
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Electrostatic role of aromatic ring stacking in the pH-sensitive modulation of a chymotrypsin-type serine protease, Achromobacter protease I.
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Prime site binding inhibitors of a serine protease: NS3/4A of hepatitis C virus.
  Biochemistry, 41, 5483-5492.  
12081498 S.Braud, B.F.Le Bonniec, C.Bon, and A.Wisner (2002).
The stratagem utilized by the plasminogen activator from the snake Trimeresurus stejnegeri to escape serpins.
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12402360 T.J.Oldfield (2002).
Data mining the protein data bank: residue interactions.
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Crystal structure of DegP (HtrA) reveals a new protease-chaperone machine.
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PDB code: 1ky9
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PDB code: 1i1i
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Cloning and characterization of the cDNA and gene for human epitheliasin.
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From proteases to proteomics.
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Molecular markers of serine protease evolution.
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Direct measurement of acylenzyme hydrolysis demonstrates rate-limiting deacylation in cleavage of physiological sequences by the processing protease Kex2.
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Structural similarities and differences in Staphylococcus aureus exfoliative toxins A and B as revealed by their crystal structures.
  Protein Sci, 9, 610-618.
PDB codes: 1dt2 1dua 1due
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Modeling of loops in protein structures.
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PDB code: 1dle
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Kinetics of beta-casein hydrolysis by wild-type and engineered trypsin.
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Lecithin retinol acyltransferase contains cysteine residues essential for catalysis.
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Serine proteinase inhibition by the active site titrant N alpha-(N, N-dimethylcarbamoyl)-alpha-azaornithine p-nitrophenyl ester. A comparative study.
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Peptide bond formation mediated by substrate mimetics. Structure-guidedoptimization of trypsin for synthesis.
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Crystal structure of bovine duodenase, a serine protease, with dual trypsin and chymotrypsin-like specificities.
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PDB code: 1euf
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Folding funnels, binding funnels, and protein function.
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Eukaryotic 20S proteasome catalytic subunit propeptides prevent active site inactivation by N-terminal acetylation and promote particle assembly.
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Unexpected crucial role of residue 225 in serine proteases.
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PDB codes: 1b7x 1thp 2thf
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The three-dimensional structure of Asp189Ser trypsin provides evidence for an inherent structural plasticity of the protease.
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Structural determinants of trypsin affinity and specificity for cationic inhibitors.
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Structural basis of profactor D activation: from a highly flexible zymogen to a novel self-inhibited serine protease, complement factor D.
  EMBO J, 18, 804-814.
PDB code: 1fdp
10500108 H.Neurath (1999).
Proteolytic enzymes, past and future.
  Proc Natl Acad Sci U S A, 96, 10962-10963.  
  10419958 J.A.Pederson, G.J.Mileski, B.C.Weimer, and J.L.Steele (1999).
Genetic characterization of a cell envelope-associated proteinase from Lactobacillus helveticus CNRZ32.
  J Bacteriol, 181, 4592-4597.  
9893995 J.Aceto, T.Kieber-Emmons, and D.B.Cines (1999).
Carboxy-terminal processing of the urokinase receptor: implications for substrate recognition and glycosylphosphatidylinositol anchor addition.
  Biochemistry, 38, 992.  
9914536 P.Hudáky, G.Kaslik, I.Venekei, and L.Gráf (1999).
The differential specificity of chymotrypsin A and B is determined by amino acid 226.
  Eur J Biochem, 259, 528-533.  
10500122 T.Takeuchi, M.A.Shuman, and C.S.Craik (1999).
Reverse biochemistry: use of macromolecular protease inhibitors to dissect complex biological processes and identify a membrane-type serine protease in epithelial cancer and normal tissue.
  Proc Natl Acad Sci U S A, 96, 11054-11061.  
9724712 A.Bevan, C.Brenner, and R.S.Fuller (1998).
Quantitative assessment of enzyme specificity in vivo: P2 recognition by Kex2 protease defined in a genetic system.
  Proc Natl Acad Sci U S A, 95, 10384-10389.  
  9568890 A.R.Khan, and M.N.James (1998).
Molecular mechanisms for the conversion of zymogens to active proteolytic enzymes.
  Protein Sci, 7, 815-836.  
9558332 G.DeSantis, P.Berglund, M.R.Stabile, M.Gold, and J.B.Jones (1998).
Site-directed mutagenesis combined with chemical modification as a strategy for altering the specificity of the S1 and S1' pockets of subtilisin Bacillus lentus.
  Biochemistry, 37, 5968-5973.  
9707558 K.P.Hopfner, E.Kopetzki, G.B.Kresse, W.Bode, R.Huber, and R.A.Engh (1998).
New enzyme lineages by subdomain shuffling.
  Proc Natl Acad Sci U S A, 95, 9813-9818.
PDB code: 1fxy
9578548 M.P.Weir, S.S.Bethell, A.Cleasby, C.J.Campbell, R.J.Dennis, C.J.Dix, H.Finch, H.Jhoti, C.J.Mooney, S.Patel, C.M.Tang, M.Ward, A.J.Wonacott, and C.W.Wharton (1998).
Novel natural product 5,5-trans-lactone inhibitors of human alpha-thrombin: mechanism of action and structural studies.
  Biochemistry, 37, 6645-6657.
PDB codes: 1awf 1awh
9521659 N.C.Rockwell, and R.S.Fuller (1998).
Interplay between S1 and S4 subsites in Kex2 protease: Kex2 exhibits dual specificity for the P4 side chain.
  Biochemistry, 37, 3386-3391.  
9558326 P.H.Liang, K.A.Brun, J.A.Feild, K.O'Donnell, M.L.Doyle, S.M.Green, A.E.Baker, M.N.Blackburn, and S.S.Abdel-Meguid (1998).
Site-directed mutagenesis probing the catalytic role of arginines 165 and 166 of human cytomegalovirus protease.
  Biochemistry, 37, 5923-5929.  
9836602 S.R.Presnell, G.S.Patil, C.Mura, K.M.Jude, J.M.Conley, J.A.Bertrand, C.M.Kam, J.C.Powers, and L.D.Williams (1998).
Oxyanion-mediated inhibition of serine proteases.
  Biochemistry, 37, 17068-17081.
PDB codes: 1bju 1bjv
  9792101 S.S.Taremi, B.Beyer, M.Maher, N.Yao, W.Prosise, P.C.Weber, and B.A.Malcolm (1998).
Construction, expression, and characterization of a novel fully activated recombinant single-chain hepatitis C virus protease.
  Protein Sci, 7, 2143-2149.  
9753436 V.De Filippis, D.Quarzago, A.Vindigni, E.Di Cera, and A.Fontana (1998).
Synthesis and characterization of more potent analogues of hirudin fragment 1-47 containing non-natural amino acids.
  Biochemistry, 37, 13507-13515.  
  9300481 A.J.Scheidig, T.R.Hynes, L.A.Pelletier, J.A.Wells, and A.A.Kossiakoff (1997).
Crystal structures of bovine chymotrypsin and trypsin complexed to the inhibitor domain of Alzheimer's amyloid beta-protein precursor (APPI) and basic pancreatic trypsin inhibitor (BPTI): engineering of inhibitors with altered specificities.
  Protein Sci, 6, 1806-1824.
PDB codes: 1ca0 1cbw 1taw
  9261433 A.Unal, T.R.Pray, M.Lagunoff, M.W.Pennington, D.Ganem, and C.S.Craik (1997).
The protease and the assembly protein of Kaposi's sarcoma-associated herpesvirus (human herpesvirus 8).
  J Virol, 71, 7030-7038.  
9306406 A.Vindigni, Q.D.Dang, and E.Di Cera (1997).
Site-specific dissection of substrate recognition by thrombin.
  Nat Biotechnol, 15, 891-895.  
9154921 C.A.Tsu, J.J.Perona, R.J.Fletterick, and C.S.Craik (1997).
Structural basis for the broad substrate specificity of fiddler crab collagenolytic serine protease 1.
  Biochemistry, 36, 5393-5401.  
  9032381 E.M.Bergmann, S.C.Mosimann, M.M.Chernaia, B.A.Malcolm, and M.N.James (1997).
The refined crystal structure of the 3C gene product from hepatitis A virus: specific proteinase activity and RNA recognition.
  J Virol, 71, 2436-2448.
PDB code: 1hav
9012804 E.Stratikos, and P.G.Gettins (1997).
Major proteinase movement upon stable serpin-proteinase complex formation.
  Proc Natl Acad Sci U S A, 94, 453-458.  
9048539 G.M.Vath, C.A.Earhart, J.V.Rago, M.H.Kim, G.A.Bohach, P.M.Schlievert, and D.H.Ohlendorf (1997).
The structure of the superantigen exfoliative toxin A suggests a novel regulation as a serine protease.
  Biochemistry, 36, 1559-1566.
PDB code: 1exf
9154920 J.J.Perona, C.A.Tsu, C.S.Craik, and R.J.Fletterick (1997).
Crystal structure of an ecotin-collagenase complex suggests a model for recognition and cleavage of the collagen triple helix.
  Biochemistry, 36, 5381-5392.
PDB code: 1azz
  9188600 J.Xu, E.Mendez, P.R.Caron, C.Lin, M.A.Murcko, M.S.Collett, and C.M.Rice (1997).
Bovine viral diarrhea virus NS3 serine proteinase: polyprotein cleavage sites, cofactor requirements, and molecular model of an enzyme essential for pestivirus replication.
  J Virol, 71, 5312-5322.  
9362477 K.P.Hopfner, H.Brandstetter, A.Karcher, E.Kopetzki, R.Huber, R.A.Engh, and W.Bode (1997).
Converting blood coagulation factor IXa into factor Xa: dramatic increase in amidolytic activity identifies important active site determinants.
  EMBO J, 16, 6626-6635.  
9048578 N.C.Rockwell, G.T.Wang, G.A.Krafft, and R.S.Fuller (1997).
Internally consistent libraries of fluorogenic substrates demonstrate that Kex2 protease specificity is generated by multiple mechanisms.
  Biochemistry, 36, 1912-1917.  
9035139 Q.D.Dang, E.R.Guinto, and E.di Cera (1997).
Rational engineering of activity and specificity in a serine protease.
  Nat Biotechnol, 15, 146-149.  
  9070434 R.J.Siezen, and J.A.Leunissen (1997).
Subtilases: the superfamily of subtilisin-like serine proteases.
  Protein Sci, 6, 501-523.  
  9260273 S.A.Gillmor, C.S.Craik, and R.J.Fletterick (1997).
Structural determinants of specificity in the cysteine protease cruzain.
  Protein Sci, 6, 1603-1611.
PDB code: 2aim
  9416603 V.Geetha, and P.J.Munson (1997).
Linkers of secondary structures in proteins.
  Protein Sci, 6, 2538-2547.  
9096314 X.Qiu, C.A.Janson, J.S.Culp, S.B.Richardson, C.Debouck, W.W.Smith, and S.S.Abdel-Meguid (1997).
Crystal structure of varicella-zoster virus protease.
  Proc Natl Acad Sci U S A, 94, 2874-2879.
PDB code: 1vzv
  8762132 A.C.Wallace, R.A.Laskowski, and J.M.Thornton (1996).
Derivation of 3D coordinate templates for searching structural databases: application to Ser-His-Asp catalytic triads in the serine proteinases and lipases.
  Protein Sci, 5, 1001-1013.  
9022671 A.R.Rezaie, and C.T.Esmon (1996).
Molecular basis of residue 192 participation in determination of coagulation protease specificity.
  Eur J Biochem, 242, 477-484.  
  8732755 B.O.Villoutreix, H.Lilja, K.Pettersson, T.Lövgren, and O.Teleman (1996).
Structural investigation of the alpha-1-antichymotrypsin: prostate-specific antigen complex by comparative model building.
  Protein Sci, 5, 836-851.  
8770196 E.Di Cera, K.P.Hopfner, and Q.D.Dang (1996).
Theory of allosteric effects in serine proteases.
  Biophys J, 70, 174-181.  
8885837 M.D.Ballinger, J.Tom, and J.A.Wells (1996).
Furilisin: a variant of subtilisin BPN' engineered for cleaving tribasic substrates.
  Biochemistry, 35, 13579-13585.  
8620861 M.Pallaoro, A.Gambacurta, L.Fiorucci, G.Mignogna, D.Barra, and F.Ascoli (1996).
cDNA cloning and primary structure of tryptase from bovine mast cells, and evidence for the expression of bovine pancreatic trypsin inhibitor mRNA in the same cells.
  Eur J Biochem, 237, 100-105.  
  8732759 T.Komiyama, H.Grøn, P.A.Pemberton, and G.S.Salvesen (1996).
Interaction of subtilisins with serpins.
  Protein Sci, 5, 874-882.  
8634240 W.S.Willett, L.S.Brinen, R.J.Fletterick, and C.S.Craik (1996).
Delocalizing trypsin specificity with metal activation.
  Biochemistry, 35, 5992-5998.  
7644467 L.Ding, G.S.Coombs, L.Strandberg, M.Navre, D.R.Corey, and E.L.Madison (1995).
Origins of the specificity of tissue-type plasminogen activator.
  Proc Natl Acad Sci U S A, 92, 7627-7631.  
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.