I went to the https://www.rcsb.org/ site, and searched for some proteins. For each entry, “unique ligands” are listed.

I understand a ligand is a molecule or ion that binds to a metal atom. I don’t understand what a unique ligand is. Why is this important? What can we do with this information?

  • $\begingroup$ It is usually helpful to search the documentation of the site in question: rcsb.org/docs/general-help/identifiers-in-pdb (section "Small molecule Instance ID"). If the documentation doesn't answer your question, then you can post here and explain what is still confusing. Ideally, you would get in touch with the administrators of the database in question to ask about their database-specific terminology. (This term is only for their database, it is not a biological concept.) $\endgroup$ Jun 12, 2021 at 17:42
  • $\begingroup$ @Maximilian Press , it doesnt mention "unique" ligand. I thought it was a biological concept hence my post. $\endgroup$
    – Harsh Dua
    Jun 13, 2021 at 22:16
  • $\begingroup$ "Small molecules such as ligands, ions, drugs, inhibitors, and individual residues (amino acids, nucleotides etc.) are found in PDB structures... For example, all ligands, water molecules, etc. nearest protein chain A will also be assigned to chain A, though each of these small molecules will have unique residue numbers. So all ligands, waters etc. near a protein with chain ID A will be assigned the same chain ID. However, each of these small molecules and ligands can be specifically located by using unique residue numbers. $\endgroup$ Jun 13, 2021 at 23:33

1 Answer 1


Your understanding is incorrect. A ligand at its most basic is a molecule that binds to another molecule. There is no requirement for metal atoms whatsoever. In the context of RCSB (home of the Protein Data Bank) we are only concerned with ligands that bind to macromolecules, the structures of which are presented there — usually proteins. The following definition is in the Glossary on the RCSB site.

ligand - A molecule that binds specifically to another molecule (usually a protein or nucleic acid) to form a complex. A ligand can be another protein, but is often a small molecule.

I’ll assume a protein here.

Original Answer

Unfortunately that Glossary doesn’t explain their usage of “unique” in this context, perhaps because it may be a recent modification. However what it would appear to me to be is an aid to distinguishing those molecules that bind in a biologically significant manner to a protein, from those molecules — metal ions and molecules like glycerol — that only bind to the protein because they are present at a high concentration in the crystallization or other preparation medium. Such molecules are likely to be present in more than one copy, i.e. not unique.

Why not just say “biological ligand” rather than “unique ligand”? The fact that only a single molecule is present doesn’t prove it is biologically significant, and this information would seem generally to be absent from submission information (in my experience). The job of the curators of PDB is to describe rather than interpret.

Edit: 17 June 2021

After inspecting several entries it became evident that my original interpretation of “unique ligand” as “individual ligand” (with a suggestion of biological relevance is incorrect. There are examples of non-biological molecules, molecules present several times, and molecules occurring in different numbers in different identical subunits all listed as “unique ligands” (@canadianer also commented on this.) The bromide ions in protein 2RC3.pdb provides an example.

I wrote to support at RCSB Protein Data Bank and I would summarize the situation as:

Any non-polymer, non-water molecule in the structure is designated in the RCSB interface (but not in the mmCIF data format) as a “unique ligand”.

The support at RCSB tacitly acknowledged the unsatisfactory nature of this and stated in their reply that “We will re-visit the use of this term.”.

As the reply was from support, I feel that it is reasonable to quote from it, but thought it better to exclude the name of the actual contact.

In short, “unique ligand” means: each of the distinct small molecule entities present in the PDB entry (i.e. a “non-polymer entity” in mmCIF nomenclature).
The word “unique” is our attempt to describe what an entity means in a brief way.  We will re-visit the use of this term.
Please note that the data is very well described in mmCIF format (https://mmcif.wwpdb.org/; https://mmcif.wwpdb.org/dictionaries/mmcif_pdbx_v50.dic/Items/_entity.id.html).
For example, here is an excerpt of the mmCIF file for the 2RC3 entry:
1 polymer     man 'CBS domain'                      15169.631 4   ? ? ? ? 
2 non-polymer syn 'BROMIDE ION'                     79.904    39  ? ? ? ? 
3 non-polymer syn NICOTINAMIDE-ADENINE-DINUCLEOTIDE 663.425   4   ? ? ? ? 
4 water       nat water                             18.015    710 ? ? ? ? 
Lines 12 and 13 correspond to the 2 “unique ligands” shown on the structure summary page.

and then is a second message:

To clarify, entity is a chemically distinct part of an mmCIF entry.
For example, looking at entry 4hhb (https://www.rcsb.org/structure/4HHB), there are 2 "unique" protein chains OR 2 protein entities.  There are 2 copies of the alpha subunit (chains A and C; one entity) and 2 copies of the beta subunit (chains B and D; a second entity). 
  • $\begingroup$ thank you so much for your explanation David. I have been searching everywhere since this post, read so much about ligands . but unique ligands yielded no results. $\endgroup$
    – Harsh Dua
    Jun 5, 2021 at 19:42
  • 1
    $\begingroup$ You are welcome. "Unique ligands" is not a set phrase, which is why you didn't find it — the PDB was just using "unique" as an adjective. Some years ago I looked through the PDB entries for 400 proteins to find ligands and had a terrible job finding which were "real" in the biological sense. Often you have to go to the original paper, and even then it may not be clear. $\endgroup$
    – David
    Jun 5, 2021 at 20:36
  • $\begingroup$ Any chance you can also explain what a unique branched monosaccharide is refering to? That yields no search results either :( $\endgroup$
    – Harsh Dua
    Jun 6, 2021 at 14:09
  • 1
    $\begingroup$ @canadianer You are right that the situation is not as simple as I stated. Earlier today I was working on the PDB site and took a random protein with two “unique ligands” to post as an example. But… So I have contacted their support for clarification and will update my post when I hear back from them. $\endgroup$
    – David
    Jun 6, 2021 at 16:58
  • 1
    $\begingroup$ I have now (17.06.21) posted an edit to my original answer following correspondence with RCSB. $\endgroup$
    – David
    Jun 17, 2021 at 11:26

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