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PDBsum entry 1t67

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protein ligands metals links
Hydrolase PDB id
1t67
Jmol
Contents
Protein chain
357 a.a. *
Ligands
B3N
Metals
_ZN
_NA ×2
Waters ×137
* Residue conservation analysis
PDB id:
1t67
Name: Hydrolase
Title: Crystal structure of human hdac8 complexed with ms-344
Structure: Histone deacetylase 8. Chain: a. Synonym: hdac8. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108.
Resolution:
2.31Å     R-factor:   0.215     R-free:   0.274
Authors: J.R.Somoza,R.J.Skene,B.A.Katz,C.Mol,J.D.Ho,A.J.Jennings,C.Lu A.Arvai,J.J.Buggy,E.Chi,J.Tang,B.-C.Sang,E.Verner,R.Wynands E.M.Leahy,D.R.Dougan,G.Snell,M.Navre,M.W.Knuth,R.V.Swanson, D.E.Mcree,L.W.Tari
Key ref:
J.R.Somoza et al. (2004). Structural snapshots of human HDAC8 provide insights into the class I histone deacetylases. Structure, 12, 1325-1334. PubMed id: 15242608 DOI: 10.1016/j.str.2004.04.012
Date:
05-May-04     Release date:   27-Jul-04    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
Q9BY41  (HDAC8_HUMAN) -  Histone deacetylase 8
Seq:
Struc:
377 a.a.
357 a.a.
Key:    PfamA domain  PfamB domain  Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class: E.C.3.5.1.98  - Histone deacetylase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     plasma membrane   6 terms 
  Biological process     mitotic cell cycle   12 terms 
  Biochemical function     hydrolase activity     11 terms  

 

 
DOI no: 10.1016/j.str.2004.04.012 Structure 12:1325-1334 (2004)
PubMed id: 15242608  
 
 
Structural snapshots of human HDAC8 provide insights into the class I histone deacetylases.
J.R.Somoza, R.J.Skene, B.A.Katz, C.Mol, J.D.Ho, A.J.Jennings, C.Luong, A.Arvai, J.J.Buggy, E.Chi, J.Tang, B.C.Sang, E.Verner, R.Wynands, E.M.Leahy, D.R.Dougan, G.Snell, M.Navre, M.W.Knuth, R.V.Swanson, D.E.McRee, L.W.Tari.
 
  ABSTRACT  
 
Modulation of the acetylation state of histones plays a pivotal role in the regulation of gene expression. Histone deacetylases (HDACs) catalyze the removal of acetyl groups from lysines near the N termini of histones. This reaction promotes the condensation of chromatin, leading to repression of transcription. HDAC deregulation has been linked to several types of cancer, suggesting a potential use for HDAC inhibitors in oncology. Here we describe the first crystal structures of a human HDAC: the structures of human HDAC8 complexed with four structurally diverse hydroxamate inhibitors. This work sheds light on the catalytic mechanism of the HDACs, and on differences in substrate specificity across the HDAC family. The structure also suggests how phosphorylation of Ser39 affects HDAC8 activity.
 
  Selected figure(s)  
 
Figure 3.
Figure 3. Interactions of HDAC8 with Inhibitors and Substrate(A) Stereo figure showing key residues in the HDAC8 active site, two TSA molecules (blue and pink), the zinc (orange), and the sodium (purple). Potential hydrogen bonds are depicted as dashed lines.(B) F[o] - F[c] simulated annealing omit maps showing the electron density for the two molecules of TSA. The maps were contoured at 2.5s and are shown within 1.8 of the TSA molecules.(C) Schematic diagram showing the binding of the hydroxamate inhibitors to HDAC8.(D) Schematic diagram showing the proposed model of how the acetylated lysine would interact with the HDAC catalytic machinery.
 
  The above figure is reprinted by permission from Cell Press: Structure (2004, 12, 1325-1334) copyright 2004.  
  Figure was selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
22230954 P.J.Watson, L.Fairall, G.M.Santos, and J.W.Schwabe (2012).
Structure of HDAC3 bound to co-repressor and inositol tetraphosphate.
  Nature, 481, 335-340.
PDB code: 4a69
21334896 W.Tang, T.Luo, E.F.Greenberg, J.E.Bradner, and S.L.Schreiber (2011).
Discovery of histone deacetylase 8 selective inhibitors.
  Bioorg Med Chem Lett, 21, 2601-2605.  
19855430 A.Villagra, E.M.Sotomayor, and E.Seto (2010).
Histone deacetylases and the immunological network: implications in cancer and inflammation.
  Oncogene, 29, 157-173.  
20337574 F.Lonardo, X.Li, A.Kaplun, A.Soubani, S.Sethi, S.Gadgeel, and S.Sheng (2010).
The natural tumor suppressor protein maspin and potential application in non small cell lung cancer.
  Curr Pharm Des, 16, 1877-1881.  
20572281 F.Thaler, M.Varasi, A.Colombo, R.Boggio, D.Munari, N.Regalia, M.G.Rozio, V.Reali, A.E.Resconi, A.Mai, S.Gagliardi, G.Dondio, S.Minucci, and C.Mercurio (2010).
Synthesis and biological characterization of amidopropenyl hydroxamates as HDAC inhibitors.
  ChemMedChem, 5, 1359-1372.  
20219112 G.Wu, C.Nan, J.C.Rollo, X.Huang, and J.Tian (2010).
Sodium valproate-induced congenital cardiac abnormalities in mice are associated with the inhibition of histone deacetylase.
  J Biomed Sci, 17, 16.  
20401613 N.Noureen, H.Rashid, and S.Kalsoom (2010).
Identification of type-specific anticancer histone deacetylase inhibitors: road to success.
  Cancer Chemother Pharmacol, 66, 625-633.  
20029090 S.L.Gantt, C.G.Joseph, and C.A.Fierke (2010).
Activation and inhibition of histone deacetylase 8 by monovalent cations.
  J Biol Chem, 285, 6036-6043.  
19475493 T.Pirali, V.Faccio, R.Mossetti, A.A.Grolla, S.Di Micco, G.Bifulco, A.A.Genazzani, and G.C.Tron (2010).
Synthesis, molecular docking and biological evaluation as HDAC inhibitors of cyclopeptide mimetics by a tandem three-component reaction and intramolecular [3+2] cycloaddition.
  Mol Divers, 14, 109-121.  
20209563 W.J.Huang, C.C.Chen, S.W.Chao, S.S.Lee, F.L.Hsu, Y.L.Lu, M.F.Hung, and C.I.Chang (2010).
Synthesis of N-hydroxycinnamides capped with a naturally occurring moiety as inhibitors of histone deacetylase.
  ChemMedChem, 5, 598-607.  
19093884 A.K.Oyelere, P.C.Chen, W.Guerrant, S.C.Mwakwari, R.Hood, Y.Zhang, and Y.Fan (2009).
Non-peptide macrocyclic histone deacetylase inhibitors.
  J Med Chem, 52, 456-468.  
18834955 A.Mai, S.Valente, A.Nebbioso, S.Simeoni, R.Ragno, S.Massa, G.Brosch, F.De Bellis, F.Manzo, and L.Altucci (2009).
New pyrrole-based histone deacetylase inhibitors: binding mode, enzyme- and cell-based investigations.
  Int J Biochem Cell Biol, 41, 235-247.  
19239270 A.Montero, J.M.Beierle, C.A.Olsen, and M.R.Ghadiri (2009).
Design, synthesis, biological evaluation, and structural characterization of potent histone deacetylase inhibitors based on cyclic alpha/beta-tetrapeptide architectures.
  J Am Chem Soc, 131, 3033-3041.  
19169274 A.Zubia, S.Ropero, D.Otaegui, E.Ballestar, M.F.Fraga, M.Boix-Chornet, M.Berdasco, A.Martinez, L.Coll-Mulet, J.Gil, F.P.Cossío, and M.Esteller (2009).
Identification of (1H)-pyrroles as histone deacetylase inhibitors with antitumoral activity.
  Oncogene, 28, 1477-1484.  
18603028 B.C.Smith, and J.M.Denu (2009).
Chemical mechanisms of histone lysine and arginine modifications.
  Biochim Biophys Acta, 1789, 45-57.  
19886628 B.He, S.Velaparthi, G.Pieffet, C.Pennington, A.Mahesh, D.L.Holzle, M.Brunsteiner, R.van Breemen, S.Y.Blond, and P.A.Petukhov (2009).
Binding ensemble profiling with photoaffinity labeling (BEProFL) approach: mapping the binding poses of HDAC8 inhibitors.
  J Med Chem, 52, 7003-7013.  
19705846 C.A.Olsen, and M.R.Ghadiri (2009).
Discovery of potent and selective histone deacetylase inhibitors via focused combinatorial libraries of cyclic alpha3beta-tetrapeptides.
  J Med Chem, 52, 7836-7846.  
19207472 D.Dayangaç-Erden, G.Bora, P.Ayhan, C.Kocaefe, S.Dalkara, K.Yelekçi, A.S.Demir, and H.Erdem-Yurter (2009).
Histone deacetylase inhibition activity and molecular docking of (e )-resveratrol: its therapeutic potential in spinal muscular atrophy.
  Chem Biol Drug Des, 73, 355-364.  
19355989 D.Wang (2009).
Computational studies on the histone deacetylases and the design of selective histone deacetylase inhibitors.
  Curr Top Med Chem, 9, 241-256.  
19528666 H.Nian, W.H.Bisson, W.M.Dashwood, J.T.Pinto, and R.H.Dashwood (2009).
Alpha-keto acid metabolites of organoselenium compounds inhibit histone deacetylase activity in human colon cancer cells.
  Carcinogenesis, 30, 1416-1423.  
19584079 J.I.Lee, H.Nian, A.J.Cooper, R.Sinha, J.Dai, W.H.Bisson, R.H.Dashwood, and J.T.Pinto (2009).
Alpha-keto acid metabolites of naturally occurring organoselenium compounds as inhibitors of histone deacetylase in human prostate cancer cells.
  Cancer Prev Res (Phila), 2, 683-693.  
19855427 L.Wang, E.F.de Zoeten, M.I.Greene, and W.W.Hancock (2009).
Immunomodulatory effects of deacetylase inhibitors: therapeutic targeting of FOXP3+ regulatory T cells.
  Nat Rev Drug Discov, 8, 969-981.  
19892411 O.H.Krämer (2009).
HDAC2: a critical factor in health and disease.
  Trends Pharmacol Sci, 30, 647-655.  
19459166 P.A.Marks, and W.S.Xu (2009).
Histone deacetylase inhibitors: Potential in cancer therapy.
  J Cell Biochem, 107, 600-608.  
19821480 P.Galletti, A.Quintavalla, C.Ventrici, G.Giannini, W.Cabri, S.Penco, G.Gallo, S.Vincenti, and D.Giacomini (2009).
Azetidinones as Zinc-Binding Groups to Design Selective HDAC8 Inhibitors.
  ChemMedChem, 4, 1991-2001.  
18725319 R.Codd, N.Braich, J.Liu, C.Z.Soe, and A.A.Pakchung (2009).
Zn(II)-dependent histone deacetylase inhibitors: suberoylanilide hydroxamic acid and trichostatin A.
  Int J Biochem Cell Biol, 41, 736-739.  
19339067 R.L.van Montfort, and P.Workman (2009).
Structure-based design of molecular cancer therapeutics.
  Trends Biotechnol, 27, 315-328.  
20161624 R.Wu, P.Hu, S.Wang, Z.Cao, and Y.Zhang (2009).
Flexibility of Catalytic Zinc Coordination in Thermolysin and HDAC8: A Born-Oppenheimer ab initio QM/MM Molecular Dynamics Study.
  J Chem Theory Comput, 6, 337.  
19388875 S.F.Sleiman, M.Basso, L.Mahishi, A.P.Kozikowski, M.E.Donohoe, B.Langley, and R.R.Ratan (2009).
Putting the 'HAT' back on survival signalling: the promises and challenges of HDAC inhibition in the treatment of neurological conditions.
  Expert Opin Investig Drugs, 18, 573-584.  
19090524 S.Schäfer, L.Saunders, S.Schlimme, V.Valkov, J.M.Wagner, F.Kratz, W.Sippl, E.Verdin, and M.Jung (2009).
Pyridylalanine-containing hydroxamic acids as selective HDAC6 inhibitors.
  ChemMedChem, 4, 283-290.  
19779641 T.L.Newkirk, A.A.Bowers, and R.M.Williams (2009).
Discovery, biological activity, synthesis and potential therapeutic utility of naturally occurring histone deacetylase inhibitors.
  Nat Prod Rep, 26, 1293-1320.  
19721249 T.Suzuki (2009).
Explorative study on isoform-selective histone deacetylase inhibitors.
  Chem Pharm Bull (Tokyo), 57, 897-906.  
19099580 A.Ashe, D.K.Morgan, N.C.Whitelaw, T.J.Bruxner, N.K.Vickaryous, L.L.Cox, N.C.Butterfield, C.Wicking, M.E.Blewitt, S.J.Wilkins, G.J.Anderson, T.C.Cox, and E.Whitelaw (2008).
A genome-wide screen for modifiers of transgene variegation identifies genes with critical roles in development.
  Genome Biol, 9, R182.  
18181121 A.P.Kozikowski, Y.Chen, A.M.Gaysin, D.N.Savoy, D.D.Billadeau, and K.H.Kim (2008).
Chemistry, biology, and QSAR studies of substituted biaryl hydroxamates and mercaptoacetamides as HDAC inhibitors-nanomolar-potency inhibitors of pancreatic cancer cell growth.
  ChemMedChem, 3, 487-501.  
18285338 A.Schuetz, J.Min, A.Allali-Hassani, M.Schapira, M.Shuen, P.Loppnau, R.Mazitschek, N.P.Kwiatkowski, T.A.Lewis, R.L.Maglathin, T.H.McLean, A.Bochkarev, A.N.Plotnikov, M.Vedadi, and C.H.Arrowsmith (2008).
Human HDAC7 harbors a class IIa histone deacetylase-specific zinc binding motif and cryptic deacetylase activity.
  J Biol Chem, 283, 11355-11363.
PDB codes: 3c0y 3c0z 3c10
18568166 A.V.Bieliauskas, and M.K.Pflum (2008).
Isoform-selective histone deacetylase inhibitors.
  Chem Soc Rev, 37, 1402-1413.  
18454196 C.C.Zhu, D.J.Bornemann, D.Zhitomirsky, E.L.Miller, M.B.O'Connor, and J.A.Simon (2008).
Drosophila histone deacetylase-3 controls imaginal disc size through suppression of apoptosis.
  PLoS Genet, 4, e1000009.  
18398905 C.Yan, Z.Xiu, X.Li, S.Li, C.Hao, and H.Teng (2008).
Comparative molecular dynamics simulations of histone deacetylase-like protein: binding modes and free energy analysis to hydroxamic acid inhibitors.
  Proteins, 73, 134-149.  
18360740 D.P.Dowling, L.Di Costanzo, H.A.Gennadios, and D.W.Christianson (2008).
Evolution of the arginase fold and functional diversity.
  Cell Mol Life Sci, 65, 2039-2055.  
19053282 D.P.Dowling, S.L.Gantt, S.G.Gattis, C.A.Fierke, and D.W.Christianson (2008).
Structural studies of human histone deacetylase 8 and its site-specific variants complexed with substrate and inhibitors.
  Biochemistry, 47, 13554-13563.
PDB codes: 3ew8 3ewf 3ezp 3ezt 3f06 3f07 3f0r
18628250 H.Nian, B.Delage, J.T.Pinto, and R.H.Dashwood (2008).
Allyl mercaptan, a garlic-derived organosulfur compound, inhibits histone deacetylase and enhances Sp3 binding on the P21WAF1 promoter.
  Carcinogenesis, 29, 1816-1824.  
18212103 K.T.Andrews, T.N.Tran, A.J.Lucke, P.Kahnberg, G.T.Le, G.M.Boyle, D.L.Gardiner, T.S.Skinner-Adams, and D.P.Fairlie (2008).
Potent antimalarial activity of histone deacetylase inhibitor analogues.
  Antimicrob Agents Chemother, 52, 1454-1461.  
18614528 M.J.Bottomley, P.Lo Surdo, P.Di Giovine, A.Cirillo, R.Scarpelli, F.Ferrigno, P.Jones, P.Neddermann, R.De Francesco, C.Steinkühler, P.Gallinari, and A.Carfí (2008).
Structural and functional analysis of the human HDAC4 catalytic domain reveals a regulatory structural zinc-binding domain.
  J Biol Chem, 283, 26694-26704.
PDB codes: 2vqj 2vqm 2vqo 2vqq 2vqv 2vqw
18256683 S.Balasubramanian, J.Ramos, W.Luo, M.Sirisawad, E.Verner, and J.J.Buggy (2008).
A novel histone deacetylase 8 (HDAC8)-specific inhibitor PCI-34051 induces apoptosis in T-cell lymphomas.
  Leukemia, 22, 1026-1034.  
18729444 S.V.Weerasinghe, G.Estiu, O.Wiest, and M.K.Pflum (2008).
Residues in the 11 A channel of histone deacetylase 1 promote catalytic activity: implications for designing isoform-selective histone deacetylase inhibitors.
  J Med Chem, 51, 5542-5551.  
18292778 X.J.Yang, and E.Seto (2008).
The Rpd3/Hda1 family of lysine deacetylases: from bacteria and yeast to mice and men.
  Nat Rev Mol Cell Biol, 9, 206-218.  
18470998 Z.A.Gurard-Levin, and M.Mrksich (2008).
The activity of HDAC8 depends on local and distal sequences of its peptide substrates.
  Biochemistry, 47, 6242-6250.  
18059533 A.Sekhavat, J.M.Sun, and J.R.Davie (2007).
Competitive inhibition of histone deacetylase activity by trichostatin A and butyrate.
  Biochem Cell Biol, 85, 751-758.  
17307359 A.V.Bieliauskas, S.V.Weerasinghe, and M.K.Pflum (2007).
Structural requirements of HDAC inhibitors: SAHA analogs functionalized adjacent to the hydroxamic acid.
  Bioorg Med Chem Lett, 17, 2216-2219.  
17721440 A.Vannini, C.Volpari, P.Gallinari, P.Jones, M.Mattu, A.Carfí, R.De Francesco, C.Steinkühler, and S.Di Marco (2007).
Substrate binding to histone deacetylases as shown by the crystal structure of the HDAC8-substrate complex.
  EMBO Rep, 8, 879-884.
PDB codes: 2v5w 2v5x
17377789 C.Hildmann, D.Riester, and A.Schwienhorst (2007).
Histone deacetylases--an important class of cellular regulators with a variety of functions.
  Appl Microbiol Biotechnol, 75, 487-497.  
17351388 C.Monneret (2007).
Histone deacetylase inhibitors for epigenetic therapy of cancer.
  Anticancer Drugs, 18, 363-370.  
17163561 F.E.Jacobsen, J.A.Lewis, and S.M.Cohen (2007).
The Design of Inhibitors for Medicinally Relevant Metalloproteins.
  ChemMedChem, 2, 152-171.  
17383217 H.Hess-Stumpp, T.U.Bracker, D.Henderson, and O.Politz (2007).
MS-275, a potent orally available inhibitor of histone deacetylases--the development of an anticancer agent.
  Int J Biochem Cell Biol, 39, 1388-1405.  
17562323 L.Di Costanzo, M.Moulin, M.Haertlein, F.Meilleur, and D.W.Christianson (2007).
Expression, purification, assay, and crystal structure of perdeuterated human arginase I.
  Arch Biochem Biophys, 465, 82-89.
PDB code: 2pll
17694086 M.Martin, R.Kettmann, and F.Dequiedt (2007).
Class IIa histone deacetylases: regulating the regulators.
  Oncogene, 26, 5450-5467.  
17325692 P.Gallinari, S.Di Marco, P.Jones, M.Pallaoro, and C.Steinkühler (2007).
HDACs, histone deacetylation and gene transcription: from molecular biology to cancer therapeutics.
  Cell Res, 17, 195-211.  
17694092 S.C.Hodawadekar, and R.Marmorstein (2007).
Chemistry of acetyl transfer by histone modifying enzymes: structure, mechanism and implications for effector design.
  Oncogene, 26, 5528-5540.  
17627667 S.Kern, D.Riester, C.Hildmann, A.Schwienhorst, and F.J.Meyer-Almes (2007).
Inhibitor-mediated stabilization of the conformational structure of a histone deacetylase-like amidohydrolase.
  FEBS J, 274, 3578-3588.  
17984971 S.Lall (2007).
Primers on chromatin.
  Nat Struct Mol Biol, 14, 1110-1115.  
  17401192 T.K.Nielsen, C.Hildmann, D.Riester, D.Wegener, A.Schwienhorst, and R.Ficner (2007).
Complex structure of a bacterial class 2 histone deacetylase homologue with a trifluoromethylketone inhibitor.
  Acta Crystallogr Sect F Struct Biol Cryst Commun, 63, 270-273.
PDB code: 2gh6
17694093 W.S.Xu, R.B.Parmigiani, and P.A.Marks (2007).
Histone deacetylase inhibitors: molecular mechanisms of action.
  Oncogene, 26, 5541-5552.  
16892355 A.Mai, S.Massa, S.Valente, S.Simeoni, R.Ragno, P.Bottoni, R.Scatena, and G.Brosch (2006).
Aroyl-pyrrolyl hydroxyamides: influence of pyrrole C4-phenylacetyl substitution on histone deacetylase inhibition.
  ChemMedChem, 1, 225-237.  
16809764 H.Lee, N.Sengupta, A.Villagra, N.Rezai-Zadeh, and E.Seto (2006).
Histone deacetylase 8 safeguards the human ever-shorter telomeres 1B (hEST1B) protein from ubiquitin-mediated degradation.
  Mol Cell Biol, 26, 5259-5269.  
17108987 I.Collins, and P.Workman (2006).
New approaches to molecular cancer therapeutics.
  Nat Chem Biol, 2, 689-700.  
17022812 N.Kamath, P.Karwowska-Desaulniers, and M.K.Pflum (2006).
Limited proteolysis of human histone deacetylase 1.
  BMC Biochem, 7, 22.  
17095247 P.A.Marks (2006).
Thioredoxin in cancer--role of histone deacetylase inhibitors.
  Semin Cancer Biol, 16, 436-443.  
16397526 S.Minucci, and P.G.Pelicci (2006).
Histone deacetylase inhibitors and the promise of epigenetic (and more) treatments for cancer.
  Nat Rev Cancer, 6, 38-51.  
16434199 W.Gu, I.Nusinzon, R.D.Smith, C.M.Horvath, and R.B.Silverman (2006).
Carbonyl- and sulfur-containing analogs of suberoylanilide hydroxamic acid: Potent inhibition of histone deacetylases.
  Bioorg Med Chem, 14, 3320-3329.  
16762839 Y.Qiu, Y.Zhao, M.Becker, S.John, B.S.Parekh, S.Huang, A.Hendarwanto, E.D.Martinez, Y.Chen, H.Lu, N.L.Adkins, D.A.Stavreva, M.Wiench, P.T.Georgel, R.L.Schiltz, and G.L.Hager (2006).
HDAC1 acetylation is linked to progressive modulation of steroid receptor-induced gene transcription.
  Mol Cell, 22, 669-679.  
16441228 ..Bruserud, C.Stapnes, K.J.Tronstad, A.Ryningen, N.Anensen, and B.T.Gjertsen (2006).
Protein lysine acetylation in normal and leukaemic haematopoiesis: HDACs as possible therapeutic targets in adult AML.
  Expert Opin Ther Targets, 10, 51-68.  
15878665 K.Vanommeslaeghe, F.De Proft, S.Loverix, D.Tourwé, and P.Geerlings (2005).
Theoretical study revealing the functioning of a novel combination of catalytic motifs in histone deacetylase.
  Bioorg Med Chem, 13, 3987-3992.  
16088937 M.Dokmanovic, and P.A.Marks (2005).
Prospects: histone deacetylase inhibitors.
  J Cell Biochem, 96, 293-304.  
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.