PDBsum entry 1cil

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Lyase(oxo-acid) PDB id
Protein chain
256 a.a. *
Waters ×197
* Residue conservation analysis
PDB id:
Name: Lyase(oxo-acid)
Title: The positions of his-64 and a bound water in human carbonic anhydrase ii upon binding three structurally related inhibitors
Structure: Carbonic anhydrase ii. Chain: a. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606
1.60Å     R-factor:   not given    
Authors: G.M.Smith,R.S.Alexander,D.W.Christianson,B.M.Mckeever, G.S.Ponticello,J.P.Springer,W.C.Randall,J.J.Baldwin, C.N.Habecker
Key ref:
G.M.Smith et al. (1994). Positions of His-64 and a bound water in human carbonic anhydrase II upon binding three structurally related inhibitors. Protein Sci, 3, 118-125. PubMed id: 8142888 DOI: 10.1002/pro.5560030115
20-Oct-93     Release date:   31-Jan-94    
Go to PROCHECK summary

Protein chain
Pfam   ArchSchema ?
P00918  (CAH2_HUMAN) -  Carbonic anhydrase 2
260 a.a.
256 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class: E.C.  - Carbonate dehydratase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: H2CO3 = CO2 + H2O
= CO(2)
+ H(2)O
      Cofactor: Zn(2+)
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     angiotensin-mediated signaling pathway   21 terms 
  Biochemical function     protein binding     5 terms  


    Added reference    
DOI no: 10.1002/pro.5560030115 Protein Sci 3:118-125 (1994)
PubMed id: 8142888  
Positions of His-64 and a bound water in human carbonic anhydrase II upon binding three structurally related inhibitors.
G.M.Smith, R.S.Alexander, D.W.Christianson, B.M.McKeever, G.S.Ponticello, J.P.Springer, W.C.Randall, J.J.Baldwin, C.N.Habecker.
The 3-dimensional structure of human carbonic anhydrase II (HCAII; EC complexed with 3 structurally related inhibitors, 1a, 1b, and 1c, has been determined by X-ray crystallographic methods. The 3 inhibitors (1a = C8H12N2O4S3) vary only in the length of the substituent on the 4-amino group: 1a, proton; 1b, methyl; and 1c, ethyl. The binding constants (Ki's) for 1a, 1b, and 1c to HCAII are 1.52, 1.88, and 0.37 nM, respectively. These structures were solved to learn if any structural cause could be found for the difference in binding. In the complex with inhibitors 1a and 1b, electron density can be observed for His-64 and a bound water molecule in the native positions. When inhibitor 1c is bound, the side chain attached to the 4-amino group is positioned so that His-64 can only occupy the alternate position and the bound water is absent. While a variety of factors contribute to the observed binding constants, the major reason 1c binds tighter to HCAII than does 1a or 1b appears to be entropy: the increase in entropy when the bound water molecule is released contributes to the increase in binding and overcomes the small penalty for putting the His-64 side chain in a higher energy state.
  Selected figure(s)  
Figure 1.
Fig. 1. Inhibitorstructures la, Ib, and IC, showing the numbering scheme used or of theinhibitors and referenced in Table 2.
Figure 4.
Fig. 4. Stereo views of the 1F, 1 - IF, I omit contoured at 20 for inhibitors la (A), Ib (B), and IC (C).
  The above figures are reprinted from an Open Access publication published by the Protein Society: Protein Sci (1994, 3, 118-125) copyright 1994.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
19261605 T.Kamenecka, J.Habel, D.Duckett, W.Chen, Y.Y.Ling, B.Frackowiak, R.Jiang, Y.Shin, X.Song, and P.Lograsso (2009).
Structure-Activity Relationships and X-ray Structures Describing the Selectivity of Aminopyrazole Inhibitors for c-Jun N-terminal Kinase 3 (JNK3) over p38.
  J Biol Chem, 284, 12853-12861.
PDB codes: 3fi2 3fi3
18335973 V.M.Krishnamurthy, G.K.Kaufman, A.R.Urbach, I.Gitlin, K.L.Gudiksen, D.B.Weibel, and G.M.Whitesides (2008).
Carbonic anhydrase as a model for biophysical and physical-organic studies of proteins and protein-ligand binding.
  Chem Rev, 108, 946.  
17665409 G.E.Höst, J.Razkin, L.Baltzer, and B.H.Jonsson (2007).
Combined enzyme and substrate design: grafting of a cooperative two-histidine catalytic motif into a protein targeted at the scissile bond in a designed ester substrate.
  Chembiochem, 8, 1570-1576.  
17284800 K.Ravikumar, and B.Sridhar (2007).
Dorzolamide hydrochloride: an antiglaucoma agent.
  Acta Crystallogr C, 63, o108-o110.  
16506782 K.M.Jude, A.L.Banerjee, M.K.Haldar, S.Manokaran, B.Roy, S.Mallik, D.K.Srivastava, and D.W.Christianson (2006).
Ultrahigh resolution crystal structures of human carbonic anhydrases I and II complexed with "two-prong" inhibitors reveal the molecular basis of high affinity.
  J Am Chem Soc, 128, 3011-3018.
PDB codes: 2foq 2fos 2fou 2fov 2foy
16477622 M.Nayal, and B.Honig (2006).
On the nature of cavities on protein surfaces: application to the identification of drug-binding sites.
  Proteins, 63, 892-906.  
12838268 S.J.Teague (2003).
Implications of protein flexibility for drug discovery.
  Nat Rev Drug Discov, 2, 527-541.  
11180334 S.Grüneberg, B.Wendt, and G.Klebe (2001).
Subnanomolar Inhibitors from Computer Screening: A Model Study Using Human Carbonic Anhydrase II.
  Angew Chem Int Ed Engl, 40, 389-393.  
  9865942 P.A.Boriack-Sjodin, S.Zeitlin, H.H.Chen, L.Crenshaw, S.Gross, A.Dantanarayana, P.Delgado, J.A.May, T.Dean, and D.W.Christianson (1998).
Structural analysis of inhibitor binding to human carbonic anhydrase II.
  Protein Sci, 7, 2483-2489.
PDB codes: 1bn1 1bn3 1bn4 1bnm 1bnn 1bnq 1bnt 1bnu 1bnv 1bnw
  9541386 T.Stams, Y.Chen, P.A.Boriack-Sjodin, J.D.Hurt, J.Liao, J.A.May, T.Dean, P.Laipis, D.N.Silverman, and D.W.Christianson (1998).
Structures of murine carbonic anhydrase IV and human carbonic anhydrase II complexed with brinzolamide: molecular basis of isozyme-drug discrimination.
  Protein Sci, 7, 556-563.
PDB codes: 1a42 2znc 3znc
9061790 C.T.Supuran, C.W.Conroy, and T.H.Maren (1997).
Is cyanate a carbonic anhydrase substrate?
  Proteins, 27, 272-278.  
9265618 F.Briganti, S.Mangani, P.Orioli, A.Scozzafava, G.Vernaglione, and C.T.Supuran (1997).
Carbonic anhydrase activators: X-ray crystallographic and spectroscopic investigations for the interaction of isozymes I and II with histamine.
  Biochemistry, 36, 10384-10392.
PDB code: 1avn
8942978 T.Stams, S.K.Nair, T.Okuyama, A.Waheed, W.S.Sly, and D.W.Christianson (1996).
Crystal structure of the secretory form of membrane-associated human carbonic anhydrase IV at 2.8-A resolution.
  Proc Natl Acad Sci U S A, 93, 13589-13594.
PDB code: 1znc
7597074 J.J.Burbaum, M.H.Ohlmeyer, J.C.Reader, I.Henderson, L.W.Dillard, G.Li, T.L.Randle, N.H.Sigal, D.Chelsky, and J.J.Baldwin (1995).
A paradigm for drug discovery employing encoded combinatorial libraries.
  Proc Natl Acad Sci U S A, 92, 6027-6031.  
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.