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Alternate locations of backbones: Difference between revisions

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At sufficiently high [[resolution]], [[Empirical models|empirical methods]] for determining macromolecular structure may detect multiple locations for some atoms, termed [[alternate locations]]. When alternate locations for backbones (main chains) deviate substantially, the backbone may separate into two pathways ("fork") and then rejoin into a single pathway.
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[[Image:Altloc-anim-cartoon-5sop.gif]]
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Animation of the alternate location 3 backbone [http://firstglance.jmol.org/conformations.htm conformations] of [[5sop]]:
<br><big>
<font color="red"><b>1</b></font>
<font color="orange"><b>2</b></font>
<font color="#00b000"><b>3</b></font>.</big><br>
[http://firstglance.jmol.org/videocapture.htm Captured] from [[FirstGlance in Jmol]].
 
<span style="background-color:black;padding:3px 3px 0px 3px;font-weight:bold;">
<span style="color:white;">Common to all conformations.&nbsp;</span>
<br>
<span style="color:Pink;">&nbsp;Pink</span></span>: [http://firstglance.jmol.org/notes.htm#singletons Singletons].
<br><br>
This is a major oversimplification of [http://firstglance.jmol.org/notes.htm#conformations all possible conformations].
 
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At sufficiently high [[resolution]], [[Empirical models|empirical methods]] for determining macromolecular structure may detect multiple locations for some atoms, termed [[alternate locations]]. When alternate locations for backbones (main chains) deviate substantially, the backbone may separate into two pathways ("fork") and then rejoin into a single pathway. [[FirstGlance in Jmol]] can color each [http://firstglance.jmol.org/conformations.htm conformation] distinctly, animate them, and isolate each. [http://firstglance.jmol.org/fg.htm?mol=5sop Explore 5sop in FirstGlance in Jmol].


==Alternate location server==
==Alternate location server==
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  ID    Method            Res  Dep Date
  ID    Method            Res  Dep Date
  9ins  X-ray diffraction 1.70  1991-10-23  min=-1.0  ave=-1.0  max=-1.0  A=48  B=48
  9ins  X-ray diffraction 1.70  1991-10-23  min=-1.0  ave=-1.0  max=-1.0  A=48  B=48
  4dgd  X-ray diffraction 1.4  2012-01-25  min=0.03  ave=4.78  max=15.87 A=84  B=84  A.CA=13  B.CA=13
  4dgd  X-ray diffraction 1.4  2012-01-25  min=0.03  ave=4.78  max=15.87 A=84  B=84  A.CA=13  B.CA=13


* '''Res''' is the resolution in &Aring;.
* '''Res''' is the resolution in &Aring;.
* '''Dep Date''' is the date of deposition into the [[PDB]].
* '''Dep Date''' is the date of deposition into the [[PDB]].
* '''min, ave, max''' are for the distances between AltLocs of '''backbone atoms only'''. "Backbone atoms" are protein alpha carbon atoms, and nucleic acid phosphorus atoms. A value of -1 is given when no backbone atoms have AltLocs.
* '''min, ave, max''' are for the distances between AltLocs of '''backbone atoms only'''. "Backbone atoms" are protein alpha carbon atoms, and nucleic acid phosphorus atoms, as defined in the AltLoc Server. A value of -1 is given when no backbone atoms have AltLocs.
* '''A''' and '''B''' are the AltLoc code characters used in these cases. Any alphanumeric characters are legal, and atoms may have more than two AltLocs.
* '''A''' and '''B''' are the AltLoc code characters used in these cases. Any alphanumeric characters are legal, and atoms may have more than two AltLocs.
* The numbers after '''A=''' and '''B=''' are the numbers of atoms with A/B AltLoc codes.
* The numbers after '''A=''' and '''B=''' are the numbers of atoms with A/B AltLoc codes.
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==Backbone Altloc Separations==
==Backbone Altloc Separations==
===X-ray diffraction===
===X-ray diffraction===
Half of all X-ray diffraction entries have AltLocs, and ~90% of those (~79,000) have backbone atom AltLocs. However, only 1,035 entries with backbone atom AltLocs (1.3%) have "substantial" '''maximum''' backbone atom AltLoc separations of >5.0 &Aring;.
<!--However, not quite ~500 entries (<1%) have "substantial" separations of some AltLoc backbone atoms, namely separations averaging >2.5 &Aring;.-->
(The [[van der Waals radii|van der Waals diameter]] of a carbon atom is 3.4 &Aring;.
The '''average''' separations for those 1,035 with maximum separations >5.0 &Aring; range from 0.14 to 91 &Aring;, with 184 entries having average separations >5.0 &Aring;.) 3,560 entries have maximum separations &ge;2.0 &Aring;, and 6,125 &ge; 1.0 &Aring;.


{| class="wikitable"
{| class="wikitable"
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==AltLoc Backbone Cases==
==AltLoc Backbone Cases==
====Case 1: Flexible active site loop broadens range of protection.====
{| class="wikitable"
{| class="wikitable"
|-
|-
| '''Case 1: Flexible active site loop broadens range of protection.''' [https://www.uniprot.org/uniprotkb/B0LJC8/entry TRIMCyp protein] mediates innate immunity to HIV by inhibiting post-entry retrovirus replication. Evidence suggests that TRIMCyp has evolved through mutations to broaden the range of retroviruses it can inhibit<ref name="4dgd">PMID: 22407016</ref>. These mutations render the active site able to assume multiple conformations. In particular, the cyclophilin-binding loop 64-74 (GGNFT HCNGT GG), flanked by double glycine pivots, exhibited flexibility<ref name="4dgd" />. A crystal structure, [[4dgd]], resolved two alternate location conformations for the loop residues 66-74, shown at right in red (AltLoc A) and orange (AltLoc B), each at about 50% occupancy.
| [https://www.uniprot.org/uniprotkb/B0LJC8/entry TRIMCyp protein] mediates innate immunity to HIV by inhibiting post-entry retrovirus replication. Evidence suggests that TRIMCyp has evolved through mutations to broaden the range of retroviruses it can inhibit<ref name="4dgd">PMID: 22407016</ref>. These mutations render the active site able to assume multiple conformations. In particular, the cyclophilin-binding loop 64-74 (GGNFT HCNGT GG), flanked by double glycine pivots, exhibited flexibility<ref name="4dgd" />. A crystal structure, [[4dgd]], resolved two alternate location conformations for the loop residues 66-74, shown at right in '''{{Font color|red|red (AltLoc A)}}''' and '''{{Font color|orange|orange (AltLoc B)}}''', each at about 50% occupancy.


Explore [http://firstglance.jmol.org/fg.htm?mol=4dgd 4DGD in FirstGlance in Jmol], which has [[Alternate_locations#Visualizing_alternate_locations|AltLoc visualization/animation capabilities]].
Explore [http://firstglance.jmol.org/fg.htm?mol=4dgd 4DGD in FirstGlance in Jmol], which has [[Alternate_locations#Visualizing_alternate_locations|AltLoc visualization/animation capabilities]].


[[#Alternate location server|AltLoc Server Report]]:<br>
<tt>4dgd  X-ray diffraction 1.4  2012-01-25  min=0.03  ave=4.78  max=15.87  A=84  B=84  A.CA=13  B.CA=13</tt>
<tt>4dgd  X-ray diffraction 1.4  2012-01-25  min=0.03  ave=4.78  max=15.87  A=84  B=84  A.CA=13  B.CA=13</tt>
| [[Image:4dgd-altlocs.png|right]]
| [[Image:4dgd-altlocs.png|right]]
|}
|}
====Case 2: Twist in a potassium channel regulates gating.====
{| class="wikitable"
|-
| rowspan=2 |
Inwardly rectifying potassium (Kir) channels that pass K+ more easily inwards than outwards have a cytoplasmic regulatory domain. A constriction in the cytoplasmic region of the pore (white, bottom) has been thought to gate potassium channels, but the ion selectivity filter (colored, top) may be equally important in gating. Crystal structures reveal alternative locations: rotation of the cytoplasmic domains relative to the selectivity filter appears to be involved in regulation of selectivity and gating<ref name="2wlk-comment">PMID: 20550927</ref><ref name="2wlk">PMID: 20564790</ref>.
Explore [http://firstglance.jmol.org/fg.htm?mol=2wlk 2WLK in FirstGlance in Jmol], which has [[Alternate_locations#Visualizing_alternate_locations|AltLoc visualization/animation capabilities]].
[[#Alternate location server|AltLoc Server Report]]:<br>
<tt>2wlk  X-ray diffraction 2.8 2009-06-24  min=1.04  ave 5.64  max 9.99  A=1500  B=1540  A.CA=202  B.CA=206
</tt>
| width=240|[[Image:2wlk-altlocs.png]]
| [[Image:2wlk-altlocs-chain-A.png]]
|-
| Gated K+ channel [[2wlk|2WLK]]. Cytoplasmic domains white; transmembrane selectivity filter domains colored: <b><span class="text-red">AltLoc A</span></b>, <b><span class="text-orange">AltLoc B</span></b>.
| Selectivity filter domain of a single chain of the tetrameric pore. <b><span class="text-red">AltLoc A</span></b>, <b><span class="text-orange">AltLoc B</span></b>.
|}
====Additional Cases====
* [http://firstglance.jmol.org/fg.htm?mol=3pga 3PGA], a glutaminase-asparaginase, has a 20-residue flexible loop that is thought to orient substrate and help to transport substrate and product from the active site.
* [http://firstglance.jmol.org/fg.htm?mol=3kqu 3KQU] illustrates a helicase ratchet translocation mechanism with its single-stranded DNA in four positions (conformations).
* The [http://firstglance.jmol.org/fg.htm?mol=4myd&au=1 asymmetric unit of 4MYD] is a trimeric enzyme, in which "two [chains] bind one or both small molecule ligands and the third in the middle is present in two C2-symmetric conformations in a 1:1 ratio without any ligands." Here you will see alternate locations representing the entire middle chain rotated close to 180 degrees.
* [http://firstglance.jmol.org/fg.htm?mol=6xkc 6XKC] is a hexamer. Two of the chains are modeled at two different angles relative to the other 4. In animation, these chains wave back and forth.


==References==
==References==
<references />
<references />

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