PDBsum entry 1wpo

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Viral protein, hydrolase PDB id
Protein chains
207 a.a. *
212 a.a. *
Waters ×249
* Residue conservation analysis
PDB id:
Name: Viral protein, hydrolase
Title: Hydrolytic enzyme human cytomegalovirus protease
Structure: Human cytomegalovirus protease. Chain: a, b. Engineered: yes
Source: Human herpesvirus 5. Human cytomegalovirus. Organism_taxid: 10359. Expressed in: escherichia coli. Expression_system_taxid: 562
Biol. unit: Dimer (from PQS)
2.00Å     R-factor:   0.221     R-free:   0.288
Authors: L.Tong
Key ref: L.Tong et al. (1996). A new serine-protease fold revealed by the crystal structure of human cytomegalovirus protease. Nature, 383, 272-275. PubMed id: 8805706
23-Jul-96     Release date:   15-Oct-97    
Go to PROCHECK summary

Protein chain
Pfam   ArchSchema ?
P16753  (PPR_HCMVA) -  Capsid scaffolding protein
708 a.a.
207 a.a.*
Protein chain
Pfam   ArchSchema ?
P16753  (PPR_HCMVA) -  Capsid scaffolding protein
708 a.a.
212 a.a.*
Key:    PfamA domain  PfamB domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 4 residue positions (black crosses)

 Enzyme reactions 
   Enzyme class: Chains A, B: E.C.  - Assemblin.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: Cleaves -Ala-|-Ser- and -Ala-|-Ala- bonds in the scaffold protein.
 Gene Ontology (GO) functional annotation 
  GO annot!
  Biological process     proteolysis   1 term 
  Biochemical function     serine-type endopeptidase activity     1 term  


Nature 383:272-275 (1996)
PubMed id: 8805706  
A new serine-protease fold revealed by the crystal structure of human cytomegalovirus protease.
L.Tong, C.Qian, M.J.Massariol, P.R.Bonneau, M.G.Cordingley, L.Lagacé.
Human cytomegalovirus (hCMV), a herpesvirus, infects up to 70% of the general population in the United States and can cause morbidity and mortality in immunosuppressed individuals (organ-transplant recipients and AIDS patients) and congenitally infected newborns. hCMV protease is essential for the production of mature infectious virions, as it performs proteolytic processing near the carboxy terminus (M-site) of the viral assembly protein precursor. hCMV protease is a serine protease, although it has little homology to other clans of serine proteases. Here we report the crystal structure of hCMV protease at 2.0 angstroms resolution, and show that it possesses a new polypeptide backbone fold. Ser 132 and His 63 are found in close proximity in the active site, confirming earlier biochemical and mutagenesis studies. The structure suggests that the third member of the triad is probably His 157. A dimer of the protease with an extensive interface is found in the crystal structure. This structure information will help in the design and optimization of inhibitors against herpesvirus proteases.

Literature references that cite this PDB file's key reference

  PubMed id Reference
19633659 T.Shahian, G.M.Lee, A.Lazic, L.A.Arnold, P.Velusamy, C.M.Roels, R.K.Guy, and C.S.Craik (2009).
Inhibition of a viral enzyme by a small-molecule dimer disruptor.
  Nat Chem Biol, 5, 640-646.  
18824507 O.D.Ekici, M.Paetzel, and R.E.Dalbey (2008).
Unconventional serine proteases: variations on the catalytic Ser/His/Asp triad configuration.
  Protein Sci, 17, 2023-2037.  
17870089 A.Lazic, D.H.Goetz, A.M.Nomura, A.B.Marnett, and C.S.Craik (2007).
Substrate modulation of enzyme activity in the herpesvirus protease family.
  J Mol Biol, 373, 913-923.
PDB code: 2pbk
17287260 E.J.Brignole, and W.Gibson (2007).
Enzymatic activities of human cytomegalovirus maturational protease assemblin and its precursor (pPR, pUL80a) are comparable: [corrected] maximal activity of pPR requires self-interaction through its scaffolding domain.
  J Virol, 81, 4091-4103.  
16799156 G.Seyit, B.Rockel, W.Baumeister, and J.Peters (2006).
Size matters for the tripeptidylpeptidase II complex from Drosophila: The 6-MDa spindle form stabilizes the activated state.
  J Biol Chem, 281, 25723-25733.  
16436711 V.Cottier, A.Barberis, and U.Lüthi (2006).
Novel yeast cell-based assay to screen for inhibitors of human cytomegalovirus protease in a high-throughput format.
  Antimicrob Agents Chemother, 50, 565-571.  
15789440 A.D.Borthwick (2005).
Design of translactam HCMV protease inhibitors as potent antivirals.
  Med Res Rev, 25, 427-452.  
16188998 A.N.Loveland, C.K.Chan, E.J.Brignole, and W.Gibson (2005).
Cleavage of human cytomegalovirus protease pUL80a at internal and cryptic sites is not essential but enhances infectivity.
  J Virol, 79, 12961-12968.  
16036911 S.A.McCartney, E.J.Brignole, K.N.Kolegraff, A.N.Loveland, L.M.Ussin, and W.Gibson (2005).
Chemical rescue of I-site cleavage in living cells and in vitro discriminates between the cytomegalovirus protease, assemblin, and its precursor, pUL80a.
  J Biol Chem, 280, 33206-33212.  
15118083 A.B.Marnett, A.M.Nomura, N.Shimba, P.R.Ortiz de Montellano, and C.S.Craik (2004).
Communication between the active sites and dimer interface of a herpesvirus protease revealed by a transition-state inhibitor.
  Proc Natl Acad Sci U S A, 101, 6870-6875.  
15273316 H.Cheng, N.Shen, J.Pei, and N.V.Grishin (2004).
Double-stranded DNA bacteriophage prohead protease is homologous to herpesvirus protease.
  Protein Sci, 13, 2260-2269.  
15205439 J.Liu, and A.Mushegian (2004).
Displacements of prohead protease genes in the late operons of double-stranded-DNA bacteriophages.
  J Bacteriol, 186, 4369-4375.  
15163756 N.Shimba, A.M.Nomura, A.B.Marnett, and C.S.Craik (2004).
Herpesvirus protease inhibition by dimer disruption.
  J Virol, 78, 6657-6665.  
14517908 A.Nayeem, S.Krystek, and T.Stouch (2003).
An assessment of protein-ligand binding site polarizability.
  Biopolymers, 70, 201-211.  
12910449 Oliveira, C.R.Guimarães, G.Barreiro, and Alencastro (2003).
Investigation of the induced-fit mechanism and catalytic activity of the human cytomegalovirus protease homodimer via molecular dynamics simulations.
  Proteins, 52, 483-491.  
12669027 D.M.Coen, and P.A.Schaffer (2003).
Antiherpesvirus drugs: a promising spectrum of new drugs and drug targets.
  Nat Rev Drug Discov, 2, 278-288.  
12163586 C.K.Chan, E.J.Brignole, and W.Gibson (2002).
Cytomegalovirus assemblin (pUL80a): cleavage at internal site not essential for virus growth; proteinase absent from virions.
  J Virol, 76, 8667-8674.  
12057200 M.Comellas-Bigler, P.Fuentes-Prior, K.Maskos, R.Huber, H.Oyama, K.Uchida, B.M.Dunn, K.Oda, and W.Bode (2002).
The 1.4 a crystal structure of kumamolysin: a thermostable serine-carboxyl-type proteinase.
  Structure, 10, 865-876.
PDB codes: 1gt9 1gtg 1gtj 1gtl
11987142 M.W.Wathen (2002).
Non-nucleoside inhibitors of herpesviruses.
  Rev Med Virol, 12, 167-178.  
11741860 N.T.Hoa, J.A.Brannigan, and S.M.Cutting (2002).
The Bacillus subtilis signaling protein SpoIVB defines a new family of serine peptidases.
  J Bacteriol, 184, 191-199.  
11814340 T.R.Pray, K.K.Reiling, B.G.Demirjian, and C.S.Craik (2002).
Conformational change coupling the dimerization and activation of KSHV protease.
  Biochemistry, 41, 1474-1482.  
11301412 A.Martinez, A.Castro, C.Gil, and C.Perez (2001).
Recent strategies in the development of new human cytomegalovirus inhibitors.
  Med Res Rev, 21, 227-244.  
11260254 K.Hara, M.Shiota, H.Kido, Y.Ohtsu, T.Kashiwagi, J.Iwahashi, N.Hamada, K.Mizoue, N.Tsumura, H.Kato, and T.Toyoda (2001).
Influenza virus RNA polymerase PA subunit is a novel serine protease with Ser624 at the active site.
  Genes Cells, 6, 87-97.  
11256477 M.Matsumoto, S.Misawa, N.Chiba, H.Takaku, and H.Hayashi (2001).
Selective nonpeptidic inhibitors of herpes simplex virus type 1 and human cytomegalovirus proteases.
  Biol Pharm Bull, 24, 236-241.  
11524687 R.Batra, R.Khayat, and L.Tong (2001).
Molecular mechanism for dimerization to regulate the catalytic activity of human cytomegalovirus protease.
  Nat Struct Biol, 8, 810-817.
PDB codes: 1jq6 1jq7
11371196 R.Khayat, R.Batra, M.J.Massariol, L.Lagacé, and L.Tong (2001).
Investigating the role of histidine 157 in the catalytic activity of human cytomegalovirus protease.
  Biochemistry, 40, 6344-6351.
PDB codes: 1id4 1iec 1ied 1ief 1ieg
11524669 W.Gibson (2001).
Action at the assemblin dimer interface.
  Nat Struct Biol, 8, 739-741.  
10801485 A.Mølgaard, S.Kauppinen, and S.Larsen (2000).
Rhamnogalacturonan acetylesterase elucidates the structure and function of a new family of hydrolases.
  Structure, 8, 373-383.
PDB codes: 1deo 1dex
10666597 C.Qian, L.Lagacé, M.J.Massariol, C.Chabot, C.Yoakim, R.Déziel, and L.Tong (2000).
A rational approach towards successful crystallization and crystal treatment of human cytomegalovirus protease and its inhibitor complex.
  Acta Crystallogr D Biol Crystallogr, 56, 175-180.  
11106384 K.Håkansson, A.H.Wang, and C.G.Miller (2000).
The structure of aspartyl dipeptidase reveals a unique fold with a Ser-His-Glu catalytic triad.
  Proc Natl Acad Sci U S A, 97, 14097-14102.
PDB codes: 1fy2 1fye
11041844 K.K.Reiling, T.R.Pray, C.S.Craik, and R.M.Stroud (2000).
Functional consequences of the Kaposi's sarcoma-associated herpesvirus protease structure: regulation of activity and dimerization by conserved structural elements.
  Biochemistry, 39, 12796-12803.
PDB code: 1fl1
10480881 C.Lee, F.Piazza, S.Brutsaert, J.Valens, I.Strehlow, M.Jarosinski, C.Saris, and C.Schindler (1999).
Characterization of the Stat5 protease.
  J Biol Chem, 274, 26767-26775.  
10522707 P.Ertl, D.Cooper, G.Allen, and M.J.Slater (1999).
2-chloro-3-substituted-1,4-naphthoquinone inactivators of human cytomegalovirus protease.
  Bioorg Med Chem Lett, 9, 2863-2866.  
9857201 A.Guarné, J.Tormo, R.Kirchweger, D.Pfistermueller, I.Fita, and T.Skern (1998).
Structure of the foot-and-mouth disease virus leader protease: a papain-like fold adapted for self-processing and eIF4G recognition.
  EMBO J, 17, 7469-7479.
PDB code: 1qol
  9767059 A.K.Patick, and K.E.Potts (1998).
Protease inhibitors as antiviral agents.
  Clin Microbiol Rev, 11, 614-627.  
9731777 L.Tong, C.Qian, M.J.Massariol, R.Déziel, C.Yoakim, and L.Lagacé (1998).
Conserved mode of peptidomimetic inhibition and substrate recognition of human cytomegalovirus protease.
  Nat Struct Biol, 5, 819-826.
PDB code: 2wpo
9756878 N.J.Tigue, and J.Kay (1998).
Autoprocessing and peptide substrates for human herpesvirus 6 proteinase.
  J Biol Chem, 273, 26441-26446.  
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.  
9871780 R.Déziel, and E.Malenfant (1998).
Inhibition of human cytomegalovirus protease N(o) with monocyclic beta-lactams.
  Bioorg Med Chem Lett, 8, 1437-1442.  
9657693 S.R.LaPlante, N.Aubry, P.R.Bonneau, D.R.Cameron, L.Lagacé, M.J.Massariol, H.Montpetit, C.Plouffe, S.H.Kawai, B.D.Fulton, Z.Chen, and F.Ni (1998).
Human cytomegalovirus protease complexes its substrate recognition sequences in an extended peptide conformation.
  Biochemistry, 37, 9793-9801.
PDB code: 1bfz
  9568891 Y.Yan, Y.Li, S.Munshi, V.Sardana, J.L.Cole, M.Sardana, C.Steinkuehler, L.Tomei, R.De Francesco, L.C.Kuo, and Z.Chen (1998).
Complex of NS3 protease and NS4A peptide of BK strain hepatitis C virus: a 2.2 A resolution structure in a hexagonal crystal form.
  Protein Sci, 7, 837-847.
PDB codes: 1jxp 1ns3
9501166 Z.H.Zhou, S.J.Macnab, J.Jakana, L.R.Scott, W.Chiu, and F.J.Rixon (1998).
Identification of the sites of interaction between the scaffold and outer shell in herpes simplex virus-1 capsids by difference electron imaging.
  Proc Natl Acad Sci U S A, 95, 2778-2783.  
  9260289 A.F.Neuwald (1997).
An unexpected structural relationship between integral membrane phosphatases and soluble haloperoxidases.
  Protein Sci, 6, 1764-1767.  
  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.  
9164453 A.Wlodawer (1997).
Deposition of macromolecular coordinates resulting from crystallographic and NMR studies.
  Nat Struct Biol, 4, 173-174.  
9667847 D.L.Flynn, N.A.Abood, and B.C.Holwerda (1997).
Recent advances in antiviral research: identification of inhibitors of the herpesvirus proteases.
  Curr Opin Chem Biol, 1, 190-196.  
  9261446 J.H.Sloan, J.M.Loutsch, S.Y.Boyce, and B.C.Holwerda (1997).
Expression and characterization of recombinant murine cytomegalovirus protease.
  J Virol, 71, 7114-7118.  
9374470 J.J.Perona, and C.S.Craik (1997).
Evolutionary divergence of substrate specificity within the chymotrypsin-like serine protease fold.
  J Biol Chem, 272, 29987-29990.  
9667874 J.P.Wery, and R.W.Schevitz (1997).
New trends in macromolecular X-ray crystallography.
  Curr Opin Chem Biol, 1, 365-369.  
  9343215 R.B.Register, and J.A.Shafer (1997).
Alterations in catalytic activity and virus maturation produced by mutation of the conserved histidine residues of herpes simplex virus type 1 protease.
  J Virol, 71, 8572-8581.  
9369473 S.S.Hoog, W.W.Smith, X.Qiu, C.A.Janson, B.Hellmig, M.S.McQueney, K.O'Donnell, D.O'Shannessy, A.G.DiLella, C.Debouck, and S.S.Abdel-Meguid (1997).
Active site cavity of herpesvirus proteases revealed by the crystal structure of herpes simplex virus protease/inhibitor complex.
  Biochemistry, 36, 14023-14029.
PDB code: 1at3
9357315 W.F.Mangel, D.L.Toledo, J.Ding, R.M.Sweet, and W.J.McGrath (1997).
Temporal and spatial control of the adenovirus proteinase by both a peptide and the viral DNA.
  Trends Biochem Sci, 22, 393-398.  
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
8898742 W.Gibson (1996).
A "picture" is worth a thousand experiments.
  Nat Med, 2, 1193-1194.  
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.